ORCID Profile
0000-0003-2930-895X
Current Organisations
Monash University
,
Monash Institute of Pharmaceutical Sciences
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biological And Medical Chemistry | Medicinal and Biomolecular Chemistry | Organic Chemical Synthesis | Biologically Active Molecules | Organic Chemistry | Pharmacology and Pharmaceutical Sciences | Biochemistry and Cell Biology | Separation Science | Basic Pharmacology | Receptors and Membrane Biology | Pharmaceutical Sciences And Pharmacy | Analytical Chemistry | Characterisation of Biological Macromolecules | Biochemistry And Cell Biology Not Elsewhere Classified | Structural Chemistry | Nanotechnology | Biomolecular Modelling and Design | Main Group Metal Chemistry | Macromolecular and Materials Chemistry | Organic Chemical Synthesis | Chemical Sciences Not Elsewhere Classified | Characterisation Of Macromolecules | Physical Chemistry (Incl. Structural) | Pharmaceutical Sciences | Signal Transduction | Basic Pharmacology | Analytical Biochemistry | Organic Chemistry Not Elsewhere Classified |
ANZSRC Socio-Economic Objective (SEO)
Treatments (e.g. chemicals, antibiotics) | Chemical sciences | Expanding Knowledge in the Biological Sciences | Other | Human Pharmaceutical Treatments (e.g. Antibiotics) | Organic industrial chemicals not classified elsewhere | Prevention and treatment of pollution | Plastics in primary forms | Neurodegenerative Disorders Related to Ageing | Crop Protection Chemicals | Cardiovascular system and diseases | Biological sciences | Scientific instrumentation | Expanding Knowledge in the Chemical Sciences | Health not elsewhere classified | Organs, diseases and abnormal conditions not elsewhere classified | Treatments (e.g. chemicals, antibiotics)
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Publications
Further investigations into the N-demethylation of oripavine using iron and stainless steel
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB01021A
Abstract: Further investigations into the direct synthesis of N-nororipavine from oripavine using iron powder under non-classical Polonovski conditions have been conducted. The stoichiometry, solvents and iron oxidation rates were found to have a dramatic effect on the rate of N-demethylation as well as product yield. Herein, we also present high-yield access to the N-demethylated product simply by employing stainless steel rather than iron powder as redox catalyst. To our knowledge, this is the first time stainless steel has been used to moderate the redox chemistry of iron in organic synthesis.
Synthesis and evaluation of new N6-substituted adenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.BMC.2010.03.047
Abstract: A number of N(6)-substituted adenosine-5'-N-methylcarboxamides were synthesised and their pharmacology, in terms of their receptor affinity, selectivity and cardioprotective effects, were explored. The first series of compounds, 4a-4f and 5a-5f, showed modest receptor affinity for the A(3)AR with K(i) values in the low to mid muM range. However, the incorporation of a 4-(2-aminoethyl)-2,6-di-tert-butylphenol group in the N(6)-position (in compounds 4g and 5g) significantly improved the affinity with K(i) values of 30 and 9 nM, respectively. Improvements in affinity, as well as selectivity were seen when a functionalized linker was introduced. The N(6)-phenyl series, compounds 7a-7d, demonstrated low to mid nanomolar receptor affinities (K(i)=2.3-45.0 nM), with 7b displaying 109-fold selectivity for the A(3)AR (vs A(1)). The N(6)-benzyl series 9a-9c also proved to be potent and selective A(3)AR agonists and the longer chain length linker 13 was tolerated at the A(3)AR without abrogation of affinity or selectivity. Cardioprotection was demonstrated by a simulated ischaemia cell culture assay, whereby 7b, 7c, 9a, 9b and 9c all showed cardioprotective effects at 100 nM comparable or better than the benchmark A(3)AR agonist IB-MECA, but which were indistinguishable by statistical analysis. For ex le, compound 9c reduced cell death by 68.0+/-3.6%.
Synthesis and Pharmacological Evaluation of Noscapine-Inspired 5-Substituted Tetrahydroisoquinolines as Cytotoxic Agents.
Publisher: American Chemical Society (ACS)
Date: 29-08-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00986
Abstract: A series of 5-substituted tetrahydroisoquinolines was synthesized via a 10-step linear synthesis to assess whether replacement of noscapine's southern isobenzofuranone with other moieties resulted in retained cytotoxic activity. One such molecule, 18g, bearing a para-methoxybenzyl functionality with N-ethylcarbamoyl substitution, produced cell-cycle arrest at the G2/M phase with an EC
Utility of iron nanoparticles and a solution-phase iron species for the N-demethylation of alkaloids
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7GC00436B
Abstract: N -Demethylation of selected N -methylalkaloids using a modified Polonovski reaction can be accomplished employing nanoscale zero-valent iron, nZVI, in isopropanol.
New 2,N6-Disubstituted adenosines: potent and selective A1 adenosine receptor agonists
Publisher: Elsevier BV
Date: 04-2002
DOI: 10.1016/S0968-0896(01)00384-4
Abstract: A number of adenosine analogues substituted in the 2- and N6-positions were synthesized and evaluated for affinity, functional potency and intrinsic activity at the A1 and A2A adenosine receptors (AR). Three classes of N6-substituents were tested norbornen-2-yl (series 1), norborn-2-yl (series 2) and 5,6-epoxynorborn-2-yl (series 3). The halogens fluoro, bromo, and iodo were evaluated as C-2 substituents. All compounds showed relatively high affinity (nanomolar) for the A1AR and high potency for inhibiting (-)isoproterenol-stimulated cAMP accumulation in hamster smooth muscle DDT1 MF-2 cells with the 2-fluoro derivatives from each series having the highest affinity. All of the derivatives showed the same intrinsic activity as CPA. At the A2AAR, all of the derivatives showed relatively low affinity and potency (micromolar) for stimulating cAMP accumulation in rat pheochromocytoma PC-12 cells. The intrinsic activity of the derivatives compared to CGS 21680 was dependent upon the halogen substituent in the C-2 position with most showing partial agonist activity. Of particular interest is 2-iodo-N6-(2S-endo-norborn-2-yl)adenosine (5e), which is over 100-fold selective for the A1AR, is a full agonist at this receptor subtype and has no detectable agonist activity at the A2AAR.
4-AMINO-1-PHENYLPYRAZOLO[3,4-D]PYRIMIDIN-6(5H)-ONE, AN ISOGUANOSINE ANALOG
Publisher: CSIRO Publishing
Date: 1991
DOI: 10.1071/CH9911001
Abstract: 5-Amino-1-phenylpyrazole-4-carboxamide was condensed with benzoyl isothiocyanate. The resulting thiourea was treated with dicyclohexylcarbodiimide and annulated with ethanolic ammonia to yield 4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6(5H)-one. This product is a 1-phenylpyrazolo[3,4-d] pyrimidine analogue of the biologically active natural product, isoguanosine.
The hybrid molecule, VCP746, is a potent adenosine A2B receptor agonist that stimulates anti-fibrotic signalling
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.BCP.2016.08.007
Abstract: We have recently described the rationally-designed adenosine receptor agonist, 4-(5-amino-4-benzoyl-3-(3-(trifluoromethyl)phenyl)thiophen-2-yl)-N-(6-(9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxylmethyl)tetrahydro-furan-2-yl)-9H-purin-6-ylamino)hexyl)benzamide (VCP746), a hybrid molecule consisting of an adenosine moiety linked to an adenosine A1 receptor (A1AR) allosteric modulator moiety. At the A1AR, VCP746 mediated cardioprotection in the absence of haemodynamic side effects such as bradycardia. The current study has now identified VCP746 as an important pharmacological tool for the adenosine A2B receptor (A2BAR). The binding and function of VCP746 at the A2BAR was rigorously characterised in a heterologous expression system, in addition to examination of its anti-fibrotic signalling in cardiac- and renal-derived cells. In FlpInCHO cells stably expressing the human A2BAR, VCP746 was a high affinity, high potency A2BAR agonist that stimulated Gs- and Gq-mediated signal transduction, with an apparent lack of system bias relative to prototypical A2BAR agonists. The distinct agonist profile may result from an atypical binding mode of VCP746 at the A2BAR, which was consistent with a bivalent mechanism of receptor interaction. In isolated neonatal rat cardiac fibroblasts (NCF), VCP746 stimulated potent inhibition of both TGF-β1- and angiotensin II-mediated collagen synthesis. Similar attenuation of TGF-β1-mediated collagen synthesis was observed in renal mesangial cells (RMC). The anti-fibrotic signalling mediated by VCP746 in NCF and RMC was selectively reversed in the presence of an A2BAR antagonist. Thus, we believe, VCP746 represents an important tool to further investigate the role of the A2BAR in cardiac (patho)physiology.
Design, synthesis and evaluation of N6-substituted 2-aminoadenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3MD00364G
Abstract: A series of N 6 -substituted 2-aminoadenosine-5′- N -methylcarboxamides were synthesized from the versatile intermediate, O 6 -(benzotriazol-1-yl)-2-amino-2′,3′- O -isopropylideneinosine-5′- N -methylcarboxamide ( 1 ) and evaluated as A 3 adenosine receptor agonists.
Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases
Publisher: American Chemical Society (ACS)
Date: 11-12-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01310
Abstract: There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
Effects of Conformational Restriction of 2-Amino-3-benzoylthiophenes on A1 Adenosine Receptor Modulation
Publisher: American Chemical Society (ACS)
Date: 31-08-2010
DOI: 10.1021/JM1008538
Abstract: 2-Amino-3-benzoylthiophenes (2A3BTs) have been widely reported to act as allosteric enhancers (AEs) at the A(1) adenosine receptor (A(1)AR). Herein we describe the synthesis of a series of 1-aminoindeno[1,2-c]thiophen-8-ones and a series of (2-aminoindeno[2,1-b]thiophen-3-yl)(phenyl)methanones as conformationally rigid analogues of the 2A3BTs. These compounds were screened using a functional assay of A(1)AR-mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact Chinese hamster ovary (CHO) cells to identify both potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, N(6)-(R-phenylisopropyl)adenosine (R-PIA). All of the 1-aminoindeno[1,2-c]thiophen-8-ones (14a-c and 17a-f) proved either to be inactive or behaved as antagonists in the functional assay. However, the (2-aminoindeno[2,1-b]thiophen-3-yl)(phenyl)methanones with para-chloro substitution (compounds 25b, 25d, and 25f) did significantly augment the R-PIA response, indicating a positive allosteric effect.
Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand
Publisher: American Chemical Society (ACS)
Date: 28-08-2015
DOI: 10.1021/ACS.JMEDCHEM.5B00585
Abstract: Recently, we have demonstrated that N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652) (1) adopts a bitopic pose at one protomer of a dopamine D2 receptor (D2R) dimer to negatively modulate the binding of dopamine at the other protomer. The 1H-indole-2-carboxamide moiety of 1 extends into a secondary pocket between the extracellular ends of TM2 and TM7 within the D2R protomer. To target this putative allosteric site, we generated and characterized fragments that include and extend from the 1H-indole-2-carboxamide moiety of 1. N-Isopropyl-1H-indole-2-carboxamide (3) displayed allosteric pharmacology and sensitivity to mutations of the same residues at the top of TM2 as was observed for 1. Using 3 as an "allosteric lead", we designed and synthesized an extensive fragment library to generate novel SAR and identify N-butyl-1H-indole-2-carboxamide (11d), which displayed both increased negative cooperativity and affinity for the D2R. These data illustrate that fragmentation of extended compounds can expose fragments with purely allosteric pharmacology.
XH-14 analogues as adenosine antagonists
Publisher: Elsevier BV
Date: 09-1998
DOI: 10.1016/S0968-0896(98)00093-5
Abstract: Analogues of the potent adenosine antagonist 5-(3'-hydroxypropyl)-7-methoxy-2-(3'-methoxy-4'- hydroxyphenyl)benzo[b]furan-3-carbaldehyde (XH-14, 1) with alternate substituents in the 2-, 5- and 7-positions have been synthesised. The affinity of these compounds for the A1 adenosine receptor has been evaluated using a [3H]CPX competitive binding assay. This structure-activity study highlighted the importance of the 3-formyl and 5-(3-hydroxypropyl) moieties for high receptor affinity.
6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M
Publisher: American Chemical Society (ACS)
Date: 14-12-2019
DOI: 10.1021/ACSCHEMNEURO.8B00613
Abstract: Targeting allosteric sites of the M
Crystal structure of (4-bromonaphthalen-2-yl) acetonitrile, C12H8BrN
Publisher: Walter de Gruyter GmbH
Date: 2001
Synthesis and Utility of 2‐Halo‐O6‐(benzotriazol‐1‐yl)‐Functionalized Purine Nucleosides
Publisher: Wiley
Date: 27-12-2010
Abstract: An efficient synthesis of 2‐halo‐ O 6 ‐(benzotriazol‐1‐yl)‐substituted purine nucleosides has been accomplished via (benzotriazol‐1‐yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP)‐mediated coupling and subsequent halogenation via diazotization of the 2‐amino group of various protected guanosines and directly from guanosine itself. These products are amenable to substitution and coupling reactions in the 2‐ and 6‐positions and, accordingly, provide efficient access to highly functionalized purine nucleosides.
Substituted 1,3-Dipropylxanthines as Irreversible Antagonists of A1 Adenosine Receptors
Publisher: American Chemical Society (ACS)
Date: 08-1994
DOI: 10.1021/JM00043A010
Abstract: This report describes the synthesis of 29 xanthines containing a chemoreactive chloroaryl, beta-chloroethylamino, alpha,beta-unsaturated carbonyl, bromoacetyl, 3-(fluorosulfonyl)benzoyl, or 4-(fluorosulfonyl)benzoyl group as part of an exocyclic 1-, 3-, or 8-substituent. The xanthines inhibited the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to the A1 adenosine receptor (A1AR) of DDT1 MF2 cells at IC50s in the low-nanomolar to low-micromolar range. Seven of the 29 analogues irreversibly inhibited the binding of [3H]CPX without changing the KD of that ligand five were 1,3-dipropylxanthines having the following reactive groups as 8-substituents: (bromoacetamido)methyl (24), (bromoacetamido)ethyl (25), (bromoacetamido)propyl (26), [4-(fluorosulfonyl)benzamido]methyl (33) or 3-[[4-(fluorosulfonyl)benzoyl]oxy]cyclopentyl (42). Both 8-cyclopentyl-3-[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (53) and 8-cyclopentyl-1,3-bis[3-[[4- (fluorosulfonyl)benzoyl]oxy]propyl]xanthine (55) inhibited [3H]CPX binding irreversibly. Five of the ligands, including 26, 33 (IC50 = 49 microM), and 53 (IC50 = 9 microM), antagonized the binding of [3H]NECA to the A2aAR of PC12 cells, but unlike binding to the A1AR, binding to the A2aAR was completely reversible. The potency of 33 (IC50 = 2 microM, 72% loss of CPX binding at 1 microM) and 53 (IC50 = 0.01 microM, 74% loss of CPX binding at 0.05 microM) and their selectivity for the A1AR suggest that those two ligands may be useful in studies of the structure and function of that receptor.
Development of Novel 4‐Arylpyridin‐2‐one and 6‐Arylpyrimidin‐4‐one Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor
Publisher: Wiley
Date: 25-09-2020
Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.XPHS.2017.05.019
Abstract: Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by
SYNTHESIS OF 5-AMINOPYRAZOLE-4-CARBONITRILES
Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/CH9890747
Abstract: A one-pot reaction between substituted hydrazines, malononitrile and triethyl orthoformate leads directly to the formation of 1-substituted 5-aminopyrazole-4-carbonitriles. The scope and limitations of this synthetic procedure are discussed in relation to the well established synthesis of these compounds via substituted hydrazines and ethoxymethylenemalononitrile.
Probe dependence of allosteric enhancers on the binding affinity of adenosine A1‐receptor agonists at rat and human A1‐receptors measured using N anoBRET
Publisher: Wiley
Date: 06-02-2020
DOI: 10.1111/BPH.14575
Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 26-11-2018
Abstract: The antitussive agent noscapine has been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamic. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. These compounds are substrates for P-glycoprotein (P-gp)-mediated extrusion from cells. Consequently, the antiproliferative activity of noscapine and a series of derivatives was measured in drug-sensitive and drug-resistant cells that overexpress P-gp. None of the noscapine derivatives displayed lower potency in cells overexpressing P-gp, thereby suggesting a lack of interaction with this pump. However, the cellular efflux of a fluorescent substrate by P-gp was potently inhibited by noscapine and most derivatives. Further investigation with purified, reconstituted P-gp demonstrated that inhibition of P-gp function was due to direct interaction of noscapine derivatives with the transporter. Moreover, coadministration of vinblastine with two of the noscapine derivatives displayed synergistic inhibition of proliferation, even in P-gp-expressing resistant cell lines. Therefore, noscapine derivatives offer a dual benefit of overcoming the significant impact of P-gp in conferring multidrug resistance and synergy with tubulin-disrupting anticancer drugs.
Novel Fused Arylpyrimidinone Based Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor
Publisher: American Chemical Society (ACS)
Date: 03-03-2016
DOI: 10.1021/ACSCHEMNEURO.6B00018
Abstract: Benzoquinazolinone 1 is a positive allosteric modulator (PAM) of the M1 muscarinic acetylcholine receptor (mAChR), which is significantly more potent than the prototypical PAM, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA). In this study, we explored the structural determinants that underlie the activity of 1 as a PAM of the M1 mAChR. We paid particular attention to the importance of the tricyclic scaffold of compound 1, for the activity of the molecule. Complete deletion of the peripheral fused benzene ring caused a significant decrease in affinity and binding cooperativity with acetylcholine (ACh). This loss of affinity was rescued with the addition of either one or two methyl groups in the 7- and/or 8-position of the quinazolin-4(3H)-one core. These results demonstrate that the tricyclic benzo[h]quinazolin-4(3H)-one core could be replaced with a quinazolin-4(3H)-one core and maintain functional affinity. As such, the quinazolin-4(3H)-one core represents a novel scaffold to further explore M1 mAChR PAMs with improved physicochemical properties.
The Design, Synthesis, and Evaluation of Novel 9-Arylxanthenedione-Based Allosteric Modulators for the δ
Publisher: American Chemical Society (ACS)
Date: 13-09-2022
DOI: 10.1021/ACS.JMEDCHEM.2C01061
Abstract: Chronic pain and depression are both widely prevalent comorbid medical conditions. While efficient, μ-opioid receptor-based medications are associated with life-threatening side effects, including respiratory depression, dependence, and addiction. The δ-opioid receptor is a promising alternative biological target for chronic pain and depression due to its significantly reduced on-target side effects compared to the μ-opioid receptor. A previous study identified two δ-opioid receptor positive allosteric modulators. Herein, we report the design of five series of compounds targeting previously unexplored regions of the originally described SAR. Analogs were assessed for their ability to potentiate the agonist response of Leu-enkephalin. Of the 30 analogs, compound
The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.BMCL.2011.04.080
Abstract: A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A(1) adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with varying the size of the cycloalkyl ring. 2-Aminothiophenes with amide and hydrazide groups in the 3-position were completely inactive in an A(1)-AR-mediated ERK1/2 phosphorylation assay, yet most of the 3-benzoyl substituted compounds exhibited allosteric effects on responses mediated by the orthosteric agonist, R-PIA. Despite finding an increase in both agonistic and allosteric activities by going from a cyclopentyl ring to a cyclohexyl ring in the 3-benzoyl series, decreases were observed when further increasing the ring size. Varying the substituents on the phenyl ring of the 3-benzoyl group also affected the activity of these compounds.
Synthesis and Pharmacological Evaluation of Dual Acting Antioxidant A2A Adenosine Receptor Agonists
Publisher: American Chemical Society (ACS)
Date: 29-03-2012
DOI: 10.1021/JM300206U
Abstract: A series of adenosine-5'-N-alkylcarboxamides and N(6)-(2,2-diphenylethyl)adenosine-5'-N-alkylcarboxamides bearing antioxidant moieties in the 2-position were synthesized from the versatile intermediate, O(6)-(benzotriazol-1-yl)-2-fluoro-2',3'-O-isopropylideneinosine-5'-N-alkylcarboxamide (1). These compounds were evaluated as A(2A) adenosine receptor (A(2A)R) agonists in a cAMP accumulation assay, and a number of potent and selective agonists were identified. Three of these compounds were evaluated further in an ischemic injury cell survival assay and a reactive oxygen species (ROS) production assay whereby 15b and 15c were shown to reduce ROS activity and cell death due to ischemia.
Screening the medicines for malaria venture Malaria Box against the plasmodium falciparum aminopeptidases, M1, M17 and M18
Publisher: Public Library of Science (PLoS)
Date: 20-02-2015
Quantification of chloride ion impurities in ionic liquids using ICP-MS analysis
Publisher: Royal Society of Chemistry (RSC)
Date: 2004
DOI: 10.1039/B408002E
The TFOS International Workshop on Contact Lens Discomfort: Report of the subcommittee on clinical trial design and outcomes
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 18-10-2013
Endo Selective Diels-Alder Reactions of Furan in Ionic Liquids
Publisher: Georg Thieme Verlag KG
Date: 2002
DOI: 10.1055/S-2002-34868
Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics
Publisher: Wiley
Date: 12-2014
DOI: 10.1111/BPH.12937
Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator N-((trans)-4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-in
Publisher: American Chemical Society (ACS)
Date: 11-06-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00192
Abstract: SB269652 (1) is a negative allosteric modulator of the dopamine D
Synthesis and Characterization of Novel 2-Amino-3-benzoylthiophene Derivatives as Biased Allosteric Agonists and Modulators of the Adenosine A1 Receptor
Publisher: American Chemical Society (ACS)
Date: 17-02-2012
DOI: 10.1021/JM201600E
Abstract: A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A(1)R mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact CHO cells to identify potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, R-PIA. Two derivatives, 8h and 8i, differing only in terms of the absence or presence of an electron-withdrawing group on the benzoyl moiety of the 2A3BT scaffold, were identified as biased allosteric agonists and positive allosteric modulators of agonist function at the adenosine A(1) receptor (A(1)R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.
Ionic liquids provide unique opportunities for oral drug delivery: structure optimization and in vivo evidence of utility
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3CC48650H
Abstract: Custom-made ILs solubilized high quantities of the poorly water-soluble drugs, danazol and itraconazole, while a danazol self-emulsifying IL formulation gave rise to higher and more prolonged exposure than the crystalline drug and a lipid formulation, respectively.
Synthesis and Pharmacological Profiling of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) as Allosteric Modulators of the M1 Muscarinic Receptor
Publisher: American Chemical Society (ACS)
Date: 17-06-2013
DOI: 10.1021/JM400540B
Abstract: Established therapy in Alzheimer's disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippoc us. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pK(B)), intrinsic efficacy (τB), and both binding (α) and functional (β) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action.
Design, synthesis and evaluation of novel 2-phenyl-3-(1H-pyrazol-4-yl)pyridine positive allosteric modulators for the M4 mAChR
Publisher: Elsevier BV
Date: 10-2023
Synthesis and adenosine receptor affinity of a series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine
Publisher: American Chemical Society (ACS)
Date: 09-1991
DOI: 10.1021/JM00113A031
Abstract: Pyrazolo[3,4-d]pyrimidines are pyrazolo analogues of purines. They have been shown to be a general class of compounds which exhibit A1 adenosine receptor affinity. Two series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine have been synthesized. The first involved substitution of the N1-position while the second involved substitution of the N5-position. Both alkyl and aryl substituents were examined. All compounds were tested for A1 adenosine receptor affinity by using a (R)-[3H]-N6-(phenylisopropyl)adenosine binding assay. The 3-chlorophenyl group showed the greatest activity in the N1-position and the butyl group produced the greatest activity in the N5-position. Combination of the best substituent in each of these positions enhanced the overall activity. The most potent compound was 4-amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6(5H)- one with an IC50 of 6.4 x 10(-6) M. Selectivity at the receptor subclasses was examined by performing an A2 adenosine receptor affinity assay with [3H]CGS 21680. This series of compounds were slightly less potent at A2 receptors. 4-Amino-5-N-butyl-1-(3-chlorophenyl-1H-pyrazolo[3,4-d]pyrimidin-6(5H)-one was the most potent compound with an IC50 of 19.2 x 10(-6) M.
Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor
Publisher: Elsevier BV
Date: 08-2014
Design, Synthesis, and Biological Evaluation of Tetra‐Substituted Thiophenes as Inhibitors of p38α MAPK
Publisher: Wiley
Date: 11-11-2014
Structure-Guided Design, Synthesis, and Evaluation of Salicylic Acid-Based Inhibitors Targeting a Selectivity Pocket in the Active Site of Human 20α-Hydroxysteroid Dehydrogenase (AKR1C1)
Publisher: American Chemical Society (ACS)
Date: 27-04-2009
DOI: 10.1021/JM9001633
Abstract: The first design, synthesis, and evaluation of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) inhibitors based on the recently published crystal structure of its ternary complex with inhibitor are reported. While the enzyme-inhibitor interactions observed in the crystal structure remain conserved with the newly designed inhibitors, the additional phenyl group of the most potent compound, 3-bromo-5-phenylsalicylic acid, targets a nonconserved hydrophobic pocket in the active site of AKR1C1 resulting in 21-fold improved potency (K(i) = 4 nM) over the structurally similar 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C2). The compound is hydrogen bonded to Tyr55, His117, and His222, and the phenyl ring forms additional van der Waals interactions with residues Leu308, Phe311, and the nonconserved Leu54 (Val in AKR1C2). Additionally, the metabolism of progesterone in AKR1C1-overexpressed cells was potently inhibited by 3-bromo-5-phenylsalicylic acid, which was effective from 10 nM with an IC(50) value equal to 460 nM.
4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M1 Muscarinic Acetylcholine Receptor
Publisher: American Chemical Society (ACS)
Date: 31-12-2015
DOI: 10.1021/ACS.JMEDCHEM.5B01562
Abstract: Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimer's and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a erse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.
Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole
Publisher: American Chemical Society (ACS)
Date: 24-07-2019
Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiLX)
Publisher: American Chemical Society (ACS)
Date: 12-06-2020
Richter cyclization and co-cyclization reactions of triazene-masked diazonium ions
Publisher: Elsevier BV
Date: 12-2010
Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum
Publisher: Portland Press Ltd.
Date: 27-09-2016
DOI: 10.1042/BCJ20160550
Abstract: Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic ‘liver stage’ and a symptomatic ‘blood stage’. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics.
The trikentrins : novel indoles from the sponge
Publisher: Elsevier BV
Date: 1986
Synthesis of natural products possessing a benzo[b]furan skeleton
Publisher: Elsevier BV
Date: 09-1998
A Structure–Activity Relationship Study of Bitopic N6-Substituted Adenosine Derivatives as Biased Adenosine A1 Receptor Agonists
Publisher: American Chemical Society (ACS)
Date: 15-02-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00047
Abstract: The adenosine A
Development of a Photoactivatable Allosteric Ligand for the M1 Muscarinic Acetylcholine Receptor
Publisher: American Chemical Society (ACS)
Date: 09-09-2014
DOI: 10.1021/CN500173X
Abstract: The field of G protein-coupled receptor drug discovery has benefited greatly from the structural and functional insights afforded by photoactivatable ligands. One G protein-coupled receptor subfamily for which photoactivatable ligands have been developed is the muscarinic acetylcholine receptor family, though, to date, all such ligands have been designed to target the orthosteric (endogenous ligand) binding site of these receptors. Herein we report the synthesis and pharmacological investigation of a novel photoaffinity label, MIPS1455 (4), designed to bind irreversibly to an allosteric site of the M1 muscarinic acetylcholine receptor a target of therapeutic interest for the treatment of cognitive deficits. MIPS1455 may be a valuable molecular tool for further investigating allosteric interactions at this receptor.
Development of Inhibitors of Plasmodium falciparum Apical Membrane Antigen 1 Based on Fragment Screening
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH13266
Abstract: Apical membrane antigen 1 (AMA1) is an essential component of the moving junction complex used by Plasmodium falciparum to invade human red blood cells. AMA1 has a conserved hydrophobic cleft that is the site of key interactions with the rhoptry neck protein complex. Our goal is to develop small molecule inhibitors of AMA1 with broad strain specificity, which we are pursuing using a fragment-based approach. In our screening c aign, we identified fragments that bind to the hydrophobic cleft with a hit rate of 5 %. The high hit rate observed strongly suggests that a druggable pocket is present within the cleft.
Ionic Liquids: The Neglected Issues
Publisher: CSIRO Publishing
Date: 2005
DOI: 10.1071/CH04272
Abstract: There has been an explosion of interest in ionic liquids in the last five years that has resulted in the discovery of a vast number of new ionic liquids with a wide range of interesting applications. Although ionic liquids are invariably described as highly stable green solvents, thorough investigations quantifying their purity, stability, biodegradability, and toxicity have lagged behind the pace of other research in the area. This review addresses these key issues and summarizes the approaches that have been developed for recycling ionic liquids.
A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
Publisher: American Chemical Society (ACS)
Date: 23-04-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01565
Abstract: Recently, a novel negative allosteric modulator (NAM) of the D
Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2RA21693K
A Structure−Activity Relationship Study of Novel Hydroxamic Acid Inhibitors around the S1 Subsite of Human Aminopeptidase N
Publisher: Wiley
Date: 22-10-2020
Front Cover: A Novel Class of N ‐Sulfonyl and N ‐Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells (ChemMedChem
Publisher: Wiley
Date: 22-11-2019
Synthesis and Biological Evaluation of Adenosines with Heterobicyclic and Polycyclic N6‐Substituents as Adenosine A1 Receptor Agonists
Publisher: Wiley
Date: 08-06-2012
Abstract: A concise synthesis of a series of N(6)-substituted adenosines with bicyclo[3.2.1]octan-6-yl and polycyclic N(6)-substituents has been developed. The adenosine A(1) receptor (A(1)R) affinity and potency of these compounds was initially assessed using competitive binding assays and cyclic adenosine monophosphate (cAMP) accumulation assays in DDT(1) MF-2 cells. The potency and receptor subtype selectivity of selected ex les was further evaluated by measuring their effects on cAMP accumulation at all human adenosine receptor subtypes expressed in CHO cells. The results of these assays indicated that all of the synthesised N(6)-substituted adenosines are full agonists at A(1) R and activate this receptor selectively over the other adenosine receptor subtypes. The two standout compounds in terms of potency were N(6)-(3-thiabicyclo[3.2.1]octan-6-yl)adenosine and N(6)-(cubanylmethyl)adenosine with EC(50) values at human A(1)R of 2.3 nM and 1.1 nM, respectively. The cubanylmethyl derivative in particular proved to be highly receptor subtype selective. These two compounds were further evaluated in a simulated ischaemia model in cultured cardiomyoblasts, where they were found to impart protective effects under hypoxic conditions that resulted in a significant reduction in cell death.
Further investigation of the N-demethylation of tertiary amine alkaloids using the non-classical Polonovski reaction
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.BMCL.2006.03.017
Abstract: The iron salt-mediated Polonovski reaction efficiently N-demethylates certain opiate alkaloids. In this process, the use of the hydrochloride salt of the tertiary N-methyl amine oxide was reported to give better yields of the desired N-demethylated product. Herein, we report further investigation into the use of N-oxide salts in the iron salt-mediated Polonovski reaction. An efficient approach for the removal of iron salts that greatly facilitates isolation and purification of the N-nor product is also described.
Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A1 Receptor in Living Cells
Publisher: American Chemical Society (ACS)
Date: 16-03-2021
Liquid Assisted Grinding for the N-Demethylation of Alkaloids
Publisher: American Chemical Society (ACS)
Date: 21-06-2018
Lanasol dyes and wool fibres. Part I: model studies on the mechanism of dye fixation in a mixed solvent system
Publisher: Elsevier BV
Date: 12-1998
Assessment of the Molecular Mechanisms of Action of Novel 4-Phenylpyridine-2-One and 6-Phenylpyrimidin-4-One Allosteric Modulators at the M1 Muscarinic Acetylcholine Receptors
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 24-04-2018
Abstract: Positive allosteric modulators (PAMs) that target the M
Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations
Publisher: American Chemical Society (ACS)
Date: 30-10-2018
DOI: 10.1021/ACS.MOLPHARMACEUT.8B00858
Abstract: The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for ex les of this compound class. Lipophilic (docusate) salt forms of erlotinib, gefitinib, ceritinib, and cabozantinib (as ex le smKIs demonstrating low aqueous solubility and high lipophilicity) were prepared and isolated as workable powder solids. In each case, the lipophilic salt exhibited high and significantly enhanced solubility in lipidic excipients (>100 mg/g) when compared to the free base or commercial salt form. Isolation as the lipophilic salt facilitated smKI loading in model lipid-based formulations at high concentration, increased in vitro solubilization at gastric and intestinal pH and in some cases increased oral absorption (∼2-fold for cabozantinib formulations in rats). Application of a lipophilic salt approach can therefore facilitate the use of lipid-based formulations for ex les of the smKI compound class where low solubility limits absorption and is a risk factor for increased variability due to food-effects.
2-Aminothiophene-3-carboxylates and carboxamides as adenosine A1 receptor allosteric enhancers
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.BMC.2005.11.018
Abstract: Three series of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene and 2-amino-5,6,7,8-tetrahydrocyclohepta[b]thiophenes with 3-carboxylates and carboxamides have been prepared using the Gewald synthesis and evaluated as A(1)AR allosteric enhancers. The structure-activity relationships of these classes of compound are described. A number of compounds, notably 7b, are more potent and efficacious than PD81,723 (1).
Synthesis, molecular structure, NMR spectroscopic and computational analysis of a selective adenosine A2A antagonist, ZM 241385
Publisher: Springer Science and Business Media LLC
Date: 27-10-2012
Investigation of novel ropinirole analogues: synthesis, pharmacological evaluation and computational analysis of dopamine D2 receptor functionalized congeners and homobivalent ligands
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4MD00066H
Abstract: This study includes the synthesis, pharmacological evaluation and molecular modeling study of novel ropinirole-based monovalent and homobivalent ligands.
Crystal structure of 4-(3'-acetoxypropyl)-6-bromo-2-methoxyphenol, С12Н15ВrО4
Publisher: Walter de Gruyter GmbH
Date: 04-1998
Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.EJMECH.2010.08.052
Abstract: The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K(i) = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC(50) value equal to 100 nM.
Crystal structure of 5-(3'-acetoxypropyl)-4-iodo-7-methoxy-2-phenyl-benzo[b]furan, C20H19IO4
Publisher: Walter de Gruyter GmbH
Date: 04-1998
Alternating Iodonium-Mediated Reaction Cascades Giving Indole- And Quinoline-Containing Polycycles
Publisher: American Chemical Society (ACS)
Date: 24-04-2008
DOI: 10.1021/OL800202U
Abstract: A simple two-step convergent protocol gives direct access to synthetic intermediate A from ortho-iodoanilines. Intermediate A can be treated with NIS in CH2Cl2 to induce novel iodonium mediated domino reaction cascade, which provides direct access to ring-fused indole compounds B. Simply by changing the reaction conditions, this protocol can be directed down an alternative domino reaction cascade to give various ring fused quinoline compounds C.
Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.CELL.2017.01.042
Abstract: The adenosine A
Adenosine receptor ligands with oxygenated N6-substituents
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0960-894X(99)00109-2
Abstract: A number of novel adenosine analogs bearing oxygenated substituents in the N6-position have been prepared and evaluated as A1 adenosine agonists. Improved conditions for the synthesis of N6-substituted adenosines and a new one pot procedure for the synthesis of 2-amino-7-oxabicyclo[2.2.1]hept-5-ene are also reported.
Biodegradable ionic liquids : Part II. Effect of the anion and toxicology
Publisher: Royal Society of Chemistry (RSC)
Date: 2005
DOI: 10.1039/B411922C
Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Publisher: eLife Sciences Publications, Ltd
Date: 13-09-2022
DOI: 10.7554/ELIFE.80813
Abstract: Plasmodium falciparum, the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the host’s main protein constituent, hemoglobin. Leucine aminopeptidase Pf A-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of Pf A-M17 to show that Pf A-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of Pf A-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate Pf A-M17 as a potential novel drug target.
Inter- and intramolecular C—H...π interactions in morphine bis(1-naphthoate)
Publisher: International Union of Crystallography (IUCr)
Date: 09-08-2003
DOI: 10.1107/S0108270103015622
Abstract: The crystal structure of morphine bis(1-naphthoate) [or 7,8-didehydro-4,5-epoxy-17-methylmorphinan-2,6-diyl bis(naphthalene-1-carboxylate)], C(39)H(31)NO(5), determined at 123 K, shows extensive C--H...pi interactions in the crystal lattice. Of particular interest is an intramolecular C--H...pi interaction within the unit cell between the two naphthoyl groups. Comparison of the opiate scaffolds of morphine bis(1-naphthoate) and morphine shows only a small increase in strain due to the steric bulk of the naphthoyl groups. The crystal packing shows distinct areas of packing for the naphthalene/aromatic groups and the opiate backbone. Extensive inter- and intramolecular C--H...pi interactions lead to a densely packed aromatic region in the crystal lattice.
VCP 746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model
Publisher: Wiley
Date: 09-2016
Abstract: VCP746 is a novel A1 adenosine receptor (A1 AR) biased agonist previously shown to be cytoprotective with no effect on heart rate. The aim of this study was to investigate the potential anti-hypertrophic effect of VCP746 in neonatal rat cardiac myocytes (NCM). NCM hypertrophy was stimulated with interleukin (IL)-1β (10 ng/mL), tumour necrosis factor (TNF)-α (10 ng/mL) or Ang II (100 nmol/L) and was assessed by (3) H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by (3) H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1 AR agonist, N(6) -cyclopentyladenosine (CPA). Further investigation with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay showed that neither CPA nor VCP746 had any effect on cell viability, confirming that the reduction in (3) H-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1β, TNF-α and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, β-MHC and α-SKA in NCM. Treatment with VCP746 at concentrations as low as 1 nmol/L suppressed mRNA expression of ANP, β-MHC and α-SKA stimulated by IL-1β, TNF-α or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A1 AR agonist, VCP746, is able to attenuate cardiac myocyte hypertrophy. As such, VCP746 is potentially useful as a pharmacological agent in attenuating cardiac remodelling, especially in the post-myocardial infarction setting, given its previously established cytoprotective properties.
Mechanistic Insights into Allosteric Structure-Function Relationships at the M1 Muscarinic Acetylcholine Receptor
Publisher: Elsevier BV
Date: 11-2014
Progress Toward the Development of Noscapine and Derivatives as Anticancer Agents
Publisher: American Chemical Society (ACS)
Date: 16-04-2015
DOI: 10.1021/JM501180V
Abstract: Many nitrogen-moiety containing alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 h of noscapine exposure at 20 μM elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation ( Proc. Natl. Acad. Sci. U. S. A. 1998 , 95 , 1601 - 1606 ). A number of noscapine analogues possessing various modifications have been described within the literature and have shown significantly improved antiprolific profiles for a large variety of cancer cell lines. Several semisynthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogues in the fight against malignant disease.
N6-(5,6-epoxynorbornyl)adenosine analogs as A1 adenosine agonists
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0960-894X(98)00668-4
Abstract: A range of related adenosines and 5'-N-ethylcarboxamidoadenosines bearing oxygenated substituents in the N6 position have been synthesised and evaluated as A1-adenosine receptor ligands. Compound 9 emerged with potent affinity (EC50 = 1.1 nM).
Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist
Publisher: Proceedings of the National Academy of Sciences
Date: 11-03-2014
Abstract: The adenosine A 1 receptor (A 1 AR) is an important target for cardioprotection, but current A 1 AR drugs are limited for this indication because of the occurrence of bradycardia as a major adverse effect mediated by the same receptor. To address this problem, we designed a ligand that simultaneously bridges two different sites on the A 1 AR the hypothesis is that this bitopic mode would result in unique receptor conformations that will signal to desirable pathways while sparing those pathways mediating undesirable effects. This mechanism was validated in native rodent cells and isolated rat atria, providing proof of concept that the design of bitopic ligands may be a path forward to separating beneficial from harmful effects mediated by the same drug target.
Grignard Reactions in Pyridinium and Phosphonium Ionic Liquids
Publisher: Wiley
Date: 28-12-2010
A new synthesis of the benzofuran adenosine antagonist XH-14
Publisher: Elsevier BV
Date: 12-1997
Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1007/S10822-012-9569-7
Abstract: We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (structurally related to SB203580) and a set of decoy compounds. Multiple protonation states and tautomers of active and decoy compounds were considered. Each docking model was evaluated using receiver operating characteristic (ROC) curves and enrichment factors. The two best performing single crystal structures were found to be 1BL7 and 2EWA, with enrichment factors of 14.1 and 13.0 at 2% of the virtual screen respectively. Ensembles of up to four receptors of similar conformations were generated, generally giving good or very good performances with high ROC AUCs and good enrichment. The 1BL7-2EWA ensemble was able to outperform each of its constituent receptors and gave high enrichment factors of 17.3, 12.0, 8.0 at 2, 5 and 10% respectively, of the virtual screen. A ROC AUC of 0.94 was obtained for this ensemble. This method may be applied to other proteins where there are a large number of inhibitor classes with different binding site conformations.
An Allosteric Modulator of the Adenosine A1 Receptor Improves Cardiac Function Following Ischaemia in Murine Isolated Hearts
Publisher: MDPI AG
Date: 12-04-2013
DOI: 10.3390/PH6040546
A Novel Class of N-Sulfonyl and N-Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells.
Publisher: Wiley
Date: 12-11-2019
Abstract: Noscapine displays weak anticancer efficacy and numerous research efforts have attempted to generate more potent noscapine analogues. These modifications included the replacement of the N-methyl group in the 6'-position with a range of substituents, where N-ethylcarbamoyl substitution was observed to possess enhanced anticancer activity. Herein, we describe advances in this area, namely the synthesis and pharmacological evaluation of a series of N-sulfonyl and N-sulfamoyl noscapine derivatives. A number of these sulfonyl-containing noscapinoids demonstrated improved activities compared to noscapine. ((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-((1-methyl-1H-imidazol-4-yl)sulfonyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline) (14 q) displayed sub-micromolar activities of 560, 980, 271 and 443 nM against MCF-7, PANC-1, MDA-MB-435 and SK-MEL-5 cells, respectively. This antiproliferative effect was also maintained against drug-resistant NCI/Adr
New potent and selective A1 adenosine receptor agonists
Publisher: Elsevier BV
Date: 09-2004
MONO-ALPHA-CARBAMOYLETHYLTHIO-SUBSTITUTED PYRAZOLO[3,4-D]PYRIMIDINES - THE POSITION OF SUBSTITUTION
Publisher: CSIRO Publishing
Date: 1991
DOI: 10.1071/CH9910753
Abstract: Pyrazolo [3,4-d] pyrimidines are a general class of compounds which exhibit adenosine receptor affinity. One particular compound, α-{6-(1α-carbamoylethylthio)-1-phenylpyrazolo-[3,4-d]pyrimidin-4-ylthio} propionamide (1a), has been shown to have antagonist activity an order of magnitude greater than theophylline at the A1 adenosine receptor. The synthesis, structural elucidation by n.m.r. spectroscopy, and adenosine receptor affinity of the mono-α- carbamoylethylthio analogue is now reported.
The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents
Publisher: Wiley
Date: 11-12-2014
Abstract: Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6', 9', 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6'-position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9'-position, regioselective O-demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9'-position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF-7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6'-ethylaminocarbonyl along with 9'-chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.
Electrochemical surface-enhanced Raman spectroscopy (E-SERS) of novel biodegradable ionic liquids
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3CP52916A
Abstract: Electrochemical SERS (E-SERS) was used for the first time to study the interfacial behavior of a class of pyridinium-based biodegradable ionic liquids at a silver nanoparticle (AgNP) electrode surface. An isomeric series of ionic liquids (IL) based on 3-butoxycarbonyl-1-methylpyridinium bis(trifluoromethanesulfonyl)imide were prepared, which have demonstrable biodegradability. It was found that all four of the isomeric ionic liquids studied exhibited excellent electrochemical stability as binary mixtures combined with methanol, with the absence of any specific redox processes occurring over nearly 3.0 V of applied potential. Normal Raman measurements of the neat isobutyl IL showed a signal rich in vibrational features, with strong contributions from both the anion and the bulky organic cation. E-SERS of the neat isobutyl IL was shown to exhibit excellent potential stability, with no potential-induced orientational change at the metal surface. When the ionic liquids were prepared as methanolic binary mixtures, dissociation of the IL ions was observed, and only the organic cation was shown to adsorb at the Ag/solution interface. The nature of the substituent on the ester group of the IL series was observed to have a significant effect on the orientation of the cation on the metal surface, based on the application of the metal surface selection rules combined with computational data. Notably, the isobutyl and sec-butyl isomers were observed to have an orientation wherein the pyridinium ring was oriented perpendicular to the surface, while the tert-butyl and n-butyl isomers were observed to have an orientation wherein the pyridinium ring was lying flat on the metal surface.
Nitrogen-Containing Ionic Liquids: Biodegradation Studies and Utility in Base-Mediated Reactions
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH14499
Abstract: Several ionic liquids (ILs) were prepared in order to study the susceptibility of various cores and substituents to biodegradability using the ‘CO2 headspace’ test (ISO 14593). Several of the ILs contained tertiary amine substituents and were tested as solvents and reagents for several base mediated processes including Suzuki–Miyaura, Sonogashira, Knoevenagel, and Morita–Baylis–Hilman reactions. It was found that although these ILs contain basic functionality, they do not promote base mediated reactions. Density functional theory molecular calculations confirmed that the protonation of these ILs is energetically unfavourable.
Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-06-2010
Abstract: Despite the identification of 2-amino-3-benzoylthiophenes (2A3BTs) as the first ex le of small-molecule allosteric potentiators of agonist function at a G protein-coupled receptor (GPCR)-the adenosine A(1) receptor-their mechanism of action is still not fully understood. We now report the mechanistic basis for the complex behaviors noted for 2A3BTs at A(1) receptors. Using a combination of membrane-based and intact-cell radioligand binding, multiple signaling assays, and a native tissue bioassay, we found that the allosteric interaction between 2A3BTs and the agonists 2-chloro-N(6)-[(3)H]cyclopentyladenosine or (-)-N(6)-(2-phenylisopropyl)adenosine (R-PIA) or the antagonist [(3)H]8-cyclopentyl-1,3-dipropylxanthine is consistent with a ternary complex model involving recognition of a single extracellular allosteric site. However, when allowed access to the intracellular milieu, 2A3BTs have a secondary action as direct G protein inhibitors this latter property is receptor-independent as it is observed in nontransfected cells and also after stimulation of another GPCR. In addition, we found that 2A3BTs can signal as allosteric agonists in their own right but show bias toward certain pathways relative to the orthosteric agonist, R-PIA. These results indicate that 2A3BTs have a dual mode of action when interacting with the A(1) receptor and that they can engender novel functional selectivity in A(1) signaling. These mechanisms need to be factored into allosteric ligand structure-activity studies.
A Novel Highly Selective Adenosine A1 Receptor Agonist VCP28 Reduces Ischemia Injury in a Cardiac Cell Line and Ischemia–Reperfusion Injury in Isolated Rat Hearts at Concentrations That Do Not Affect
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2010
Biodegradable ionic liquids : Part III. The first readily biodegradable ionic liquids
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B516206H
Positive Allosteric Modulation of the Muscarinic M1Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 14-09-2016
Abstract: Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M
Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold
Publisher: American Chemical Society (ACS)
Date: 16-01-2015
DOI: 10.1021/JM501402X
Abstract: We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a erse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for fragment libraries.
Design and Preparation of Room-Temperature Ionic Liquids Containing Biodegradable Side Chains
Publisher: CSIRO Publishing
Date: 2002
DOI: 10.1071/CH02148
Abstract: Novel room-temperature ionic liquids with potential sites of enzymatic hydrolysis have been prepared and tested for biodegradable properties.
Synthesis of 2-Substituted 3-Acylbenzo[b]furans via the Palladium Catalysed Carbonylative Cyclisation of ortho-Hydroxytolans
Publisher: Georg Thieme Verlag KG
Date: 07-1999
DOI: 10.1055/S-1999-2764
Scaffold-Divergent Synthesis of Ring-Fused Indoles, Quinolines, and Quinolones via Iodonium-Induced Reaction Cascades
Publisher: American Chemical Society (ACS)
Date: 09-05-2013
DOI: 10.1021/JO400125P
Abstract: N-(2-Iodophenyl)imines A are readily formed from Schiff's base condensation of 2-iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold- ergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring-fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed.
Driving antimalarial design through understanding of target mechanism
Publisher: Portland Press Ltd.
Date: 09-2020
DOI: 10.1042/BST20200224
Abstract: Malaria continues to be a global health threat, affecting approximately 219 million people in 2018 alone. The recurrent development of resistance to existing antimalarials means that the design of new drug candidates must be carefully considered. Understanding of drug target mechanism can dramatically accelerate early-stage target-based development of novel antimalarials and allows for structural modifications even during late-stage preclinical development. Here, we have provided an overview of three promising antimalarial molecular targets, PfDHFR, PfDHODH and PfA-M1, and their associated inhibitors which demonstrate how mechanism can inform drug design and be effectively utilised to generate compounds with potent inhibitory activity.
Structural Features of Iperoxo–BQCA Muscarinic Acetylcholine Receptor Hybrid Ligands Determining Subtype Selectivity and Efficacy
Publisher: American Chemical Society (ACS)
Date: 14-12-2021
DOI: 10.1021/ACSCHEMNEURO.1C00572
Abstract: Selective agonists for the human M
Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions.
Publisher: American Chemical Society (ACS)
Date: 28-06-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00757
Abstract: Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite
Novel Irreversible Agonists Acting at the A1 Adenosine Receptor
Publisher: American Chemical Society (ACS)
Date: 13-12-2016
DOI: 10.1021/ACS.JMEDCHEM.6B01561
Abstract: The A
Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from plasmodium falciparum
Publisher: American Chemical Society (ACS)
Date: 13-06-2013
DOI: 10.1021/JM4005972
Abstract: The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.
Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D
Publisher: American Chemical Society (ACS)
Date: 03-10-2019
DOI: 10.1021/ACS.JMEDCHEM.9B00864
Abstract: Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D
Further studies on the biodegradation of ionic liquids
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0GC00082E
1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure
Publisher: Wiley
Date: 16-07-2021
Abstract: Since the revelation of noscapine's weak anti‐mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6′, and 9′‐positions, though the 1,3‐benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3‐benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multi‐functionalised noscapine derivatives that also possessed modifications previously shown to promote anti‐proliferative activity in the 1‐, 6′‐ and 9′‐positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino‐containing analogue 20 as potent cytotoxic agents with EC 50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF‐7) cells. Compound 20 also exhibited EC 50 values of μM against melanoma, non‐small cell lung carcinoma, and cancers of the brain, kidney and breast in an NCI screen. Furthermore, compounds 14 e and 20 inhibit tubulin polymerisation and are not vulnerable to the overexpression of resistance conferring P‐gp efflux pumps in drug‐resistant breast cancer cells (NCI ADR/RES ). We also conducted X‐ray crystallography studies that yielded the high‐resolution structure of 14 e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.
The synthesis of the novel adenosine agonists, exo - and endo - N 6 -(5,6-epoxynorborn-2-yl)adenosine
Publisher: Elsevier BV
Date: 03-1996
A Multi-Step Continuous Flow Process for the N-Demethylation of Alkaloids
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH12463
Abstract: Dextromethorphan was N-demethylated using the non-classical Polonovski reaction under continuous flow conditions, in two steps: initial N-oxidation with m-chloroperbenzoic acid followed by iron-catalysed N-demethylation of the resulting N-oxide.
Effect of linker length and composition on heterobivalent ligand-mediated receptor cross-talk between the A1 adenosine and β2 adrenergic receptors
Publisher: Wiley
Date: 18-09-2013
Abstract: Heterobivalent ligands that possess pharmacophores designed to interact with both the A1 adenosine receptor (A1 AR) and the β2 adrenergic receptor (β2 AR) were prepared. More specifically, these ligands contain an adenosine moiety that is linked via its N(6) -position to the amino group of the saligenin-substituted ethanolamine moiety present in the well-known β2 AR agonist, salbutamol. The affinities of these ligands were determined at both receptors and found to vary with linker length and composition. With all compounds, affinity and functional potencies were found to have selectivity for the A1 AR over the β2 AR. In all cases, cAMP accumulation (a β2 AR-mediated response) was mainly observed when the A1 AR was blocked or its function decreased by pertussis toxin or chronic agonist treatment. This suggests that heterobivalent compounds for receptors that mediate opposite responses might be useful for elucidating the mechanisms of receptor cross-talk and how this interaction, in terms of responsiveness, may change under pathophysiological conditions.
A Monod-Wyman-Changeux Mechanism Can Explain G Protein-coupled Receptor (GPCR) Allosteric Modulation
Publisher: Elsevier BV
Date: 2012
Synthesis and Pharmacological Evaluation of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) Designed to Bind Irreversibly to an Allosteric Site of the M1 Muscarinic Acetylcholine Recep
Publisher: American Chemical Society (ACS)
Date: 05-06-2014
DOI: 10.1021/JM500556A
Abstract: Activation of the M1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site ideally, by co-crystallization with the M1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.
Role of the Second Extracellular Loop of the Adenosine A1 Receptor on Allosteric Modulator Binding, Signaling, and Cooperativity
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 28-09-2016
Abstract: Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders however, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity, and efficacy. Docking and molecular dynamics (MD) simulations were performed using an A1AR homology model based on an agonist-bound A2AAR structure. Substitution of E172ECL2 for alanine reduced the affinity of the allosteric modulators PD81723 and VCP171 for the unoccupied A1AR. Residues involved in cooperativity with the orthosteric agonist NECA were different in PD81723 and VCP171 positive cooperativity between PD81723 and NECA was reduced on alanine substitution of a number of ECL2 residues, including E170ECL2 and K173ECL2, whereas mutation of W146ECL2 and W156ECL2 decreased VCP171 cooperativity with NECA. Molecular modeling localized a likely allosteric pocket for both modulators to an extracellular vestibule that overlaps with a region used by orthosteric ligands as they transit into the canonical A1AR orthosteric site. MD simulations confirmed a key interaction between E172ECL2 and both modulators. Bound PD81723 is flanked by another residue, E170ECL2, which forms hydrogen bonds with adjacent K168ECL2 and K173ECL2. Collectively, our data suggest E172ECL2 is a key allosteric ligand-binding determinant, whereas hydrogen-bonding networks within the extracellular vestibule may facilitate the transmission of cooperativity between orthosteric and allosteric sites.
Fluorescently Labeled Morphine Derivatives for Bioimaging Studies
Publisher: American Chemical Society (ACS)
Date: 10-01-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01811
Abstract: Opioids, like morphine, are the mainstay analgesics for the treatment and control of pain. Despite this, they often exhibit severe side effects that limit dose patients often become tolerant and dependent on these drugs, which remains a major health concern. The analgesic actions of opioids are primarily mediated via the μ-opioid receptor, a member of the G protein-coupled receptor superfamily. Thus far, development of small molecule fluorescent ligands for this receptor has resulted in antagonists, somewhat limiting the use of these probes. Herein, we describe our work on the development of a small molecule fluorescent probe based on the clinically used opiate morphine and initial characterization of its behavior in cell-based assays.
The role of kinetic context in apparent biased agonism at GPCRs
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NCOMMS10842
Abstract: Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D 2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.
Synthesis and Pharmacological Evaluation of Heterocyclic Carboxamides: Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor with Weak Agonist Activity and Diverse Modu
Publisher: American Chemical Society (ACS)
Date: 15-03-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01812
Abstract: Targeting allosteric sites at M
Reverse Engineering of the Selective Agonist TBPB Unveils Both Orthosteric and Allosteric Modes of Action at the M1 Muscarinic Acetylcholine Receptor
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 24-06-2013
Abstract: Recent interest in the M₁ muscarinic acetylcholine (ACh) receptor (mAChR) has led to the discovery of various selective agonists for the receptor. The novel selective agonist 1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1 (TBPB) displays unprecedented functional selectivity at the M₁ mAChR. This functional selectivity has been described to stem from sole interaction with an allosteric site, although the evidence for such a mechanism is equivocal. To delineate TBPB's mechanism of action, several truncated variants of TBPB were synthesized and characterized. Binding experiments with [³H]N-methylscopolamine at the M₁, M₂, M₃, and M₄ mAChRs revealed radioligand displacement in a manner consistent with a competitive binding mode at the orthosteric site by TBPB and fragment derivatives. Cell-based functional assays of fragment derivatives of TBPB identified both agonistic and antagonistic moieties, one of which, 1-(1-cyclohexylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-1 (VCP794), lost agonistic selectivity for the M₁ mAChR. Further interaction experiments between TBPB or its antagonist fragments with ACh also indicated a mechanism consistent with competitive binding at mAChRs. However, interaction with an allosteric site by an antagonist fragment of TBPB was demonstrated via its ability to retard radioligand dissociation. To reconcile this dual orthosteric/allosteric pharmacological behavior, we propose that TBPB is a bitopic ligand, interacting with both the orthosteric site and an allosteric site, at the M₁ mAChR. This mechanism may also be the case for other selective agonists for mAChRs, and should be taken into consideration in the profiling and classification of new novel selective agonists for this receptor family.
Structure-based development of potent Plasmodium falciparum M1 and M17 aminopeptidase selective and dual inhibitors via S1′-region optimisation
Publisher: Elsevier BV
Date: 02-2023
(1,3-Benzo[d]dioxol-5-yl)(2-pyridyl)methyl cyanide
Publisher: International Union of Crystallography (IUCr)
Date: 10-01-2001
Examining the Role of the Linker in Bitopic N6-Substituted Adenosine Derivatives Acting as Biased Adenosine A1 Receptor Agonists
Publisher: American Chemical Society (ACS)
Date: 22-06-2022
The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions
Publisher: Springer Science and Business Media LLC
Date: 19-01-2018
DOI: 10.1038/S41598-018-19642-1
Abstract: Sodium ions (Na + ) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D 2 receptor (D 2 R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na + to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D 2 R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP). In this study, we find that the presence of a Na + within the conserved Na + -binding pocket is required for the action of SB269652. Using fragments of SB269652 and novel full-length analogues, we show that Na + is required for the high affinity binding of the tetrahydroisoquinoline moiety within the OBS, and that the interaction of the indole-2-carboxamide moiety with the SBP determines the degree of Na + -sensitivity. Thus, we extend our understanding of the mode of action of this novel class of NAM by showing it acts synergistically with Na + to modulate the binding of orthosteric ligands at the D 2 R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts.
Synthesis of Thieno‐Fused Heterocycles through Reiterative Iodocyclization
Publisher: Wiley
Date: 06-05-2014
Lanasol dyes and wool fibres. part II: model studies on the mechanism of dye fixation in an aqueous system
Publisher: Elsevier BV
Date: 12-1998
Synthesis and Pharmacological Evaluation of Dual Acting Ligands Targeting the Adenosine A2A and Dopamine D2 Receptors for the Potential Treatment of Parkinson’s Disease
Publisher: American Chemical Society (ACS)
Date: 24-12-2014
DOI: 10.1021/JM501254D
Abstract: A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.
Efficient Iron-Catalyzed N-Demethylation of Tertiary Amine-N-oxides under Oxidative Conditions
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/CH11320
Abstract: An investigation into the influence of oxidative conditions on the efficiency of opiate N-demethylation using iron powder has been carried out under non-classical Polonovski conditions. This approach involves a two-step process of N-oxidation and subsequent treatment of the intermediate N-oxide hydrochloride with the redox catalyst. Significant improvements in rate and yield have been realized for these reactions in the presence of molecular oxygen. In this context, further rate enhancement was achieved by the judicious addition of small amounts of ferric ions, leading to a concomitant reduction in the amount of the zero-valent iron primary catalyst that is required. This has led to a generalized improved methodology for the N-demethylation of oripavine, codeine, morphine, and thebaine. This protocol can also be carried out in one-pot without the need to isolate the intermediate N-oxide.
Efficient N-Demethylation of Opiate Alkaloids Using a Modified Nonclassical Polonovski Reaction
Publisher: American Chemical Society (ACS)
Date: 12-11-2003
DOI: 10.1021/JO035243Z
Abstract: A modified Polonovski reaction has been employed to N-demethylate several opiate alkaloids in moderate to high yield. This method provides an alternative to traditional N-demethylation procedures which utilize toxic reagents such as cyanogen bromide or expensive reagents such as vinyl chloroformate. The current synthesis involves N-oxide formation, isolation of the corresponding N-oxide hydrochloride, and an FeSO(4).7H(2)O mediated Polonovski reaction to afford the desired secondary amine.
Ionic Liquid Forms of Weakly Acidic Drugs in Oral Lipid Formulations: Preparation, Characterization, in Vitro Digestion, and in Vivo Absorption Studies
Publisher: American Chemical Society (ACS)
Date: 10-10-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.7B00442
Abstract: This study aimed to transform weakly acidic poorly water-soluble drugs (PWSD) into ionic liquids (ILs) to promote solubility in, and the utility of, lipid-based formulations. Ionic liquids (ILs) were formed directly from tolfenamic acid (Tolf), meclofenamic acid, diclofenac, and ibuprofen by pairing with lipophilic counterions. The drug-ILs were obtained as liquids or low melting solids and were significantly more soluble (either completely miscible or highly soluble) in lipid based, self-emulsifying drug delivery systems (SEDDS) when compared to the equivalent free acid. In vivo assessment of a SEDDS lipid solution formulation of Tolf didecyldimethylammonium salt and the same formulation of Tolf free acid at low dose (18 mg/kg, where the free acid was soluble in the SEDDS), resulted in similar absorption profiles and overall exposure. At high dose (100 mg/kg), solution SEDDS formulations of the Tolf ILs (didecyldimethylammonium, butyldodecyldimethylammonium or didecylmethylammonium salts) were possible, but the lower lipid solubility of Tolf free acid dictated that administration of the free acid was only possible as a suspension in the SEDDS formulation or as an aqueous suspension. Under these conditions, total drug plasma exposure was similar for the IL formulations and the free acid, but the plasma profiles were markedly different, resulting in flatter, more prolonged exposure profiles and reduced C
A new mechanism of allostery in a G protein–coupled receptor dimer
Publisher: Springer Science and Business Media LLC
Date: 10-08-2014
7-Selenabicyclo[2.2.1]heptane
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2CC34984A
Abstract: Thermolysis of a benzene solution of N-[4-(p-(methoxybenzyl)seleno)cyclohexanoyl]-N,S-dimethyldithiocarbonate affords the hitherto unknown 7-selenabicyclo[2.2.1]heptane in 48% conversion and in 20% yield after chromatography. G3(MP2)-RAD calculations predict a rate constant of 5 × 10(4) s(-1) at 80 °C (3.8 × 10(6) s(-1) at 200 °C) for the intramolecular homolytic substitution process involved in this cyclization.
Determination of psilocin and psilocybin using flow injection analysis with acidic potassium permanganate and tris(2,2′-bipyridyl)ruthenium(II) chemiluminescence detection respectively
Publisher: Elsevier BV
Date: 15-08-2005
DOI: 10.1016/J.TALANTA.2004.11.038
Abstract: A simple, rapid and sensitive method for the determination of psilocin and psilocybin is described. This is the first report on the determination of psilocin and psilocybin using flow injection analysis with acidic potassium permanganate and tris(2,2'-bipyridyl)ruthenium(II) chemiluminescence. The limits of detection (signal-to-noise ratio=3) are 9x10(-10)M and 3x10(-10)M for psilocin and psilocybin, respectively. A concise synthetic route for psilocin in three steps from readily available starting materials is also described. The structures were elucidated on the basis of spectroscopic data.
Differential A1‐adenosine receptor reserve for inhibition of cyclic AMP accumulation and G‐protein activation in DDT1 MF‐2 cells
Publisher: Wiley
Date: 07-2000
An expedient synthesis of N6-substituted-5′-modified adenosines
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.BMCL.2006.06.019
Abstract: Herein we report a short and efficient synthesis of N(6)-substituted 5'-modified adenosines, which was achieved in four steps from 2',3',5'-tris-O-(tert-butyldimethylsilyl)inosine.
Synthesis and biological evaluation of N-substituted noscapine analogues
Publisher: Wiley
Date: 10-10-2012
Abstract: Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule-modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6'-substituted noscapine derivatives. To underpin this structure-activity study, an efficient synthesis of N-nornoscapine and its subsequent reduction to the cyclic ether derivative of N-nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N-alkyl, N-acyl, N-carbamoyl, N-thiocarbamoyl, and N-carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell-cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF-7), and colon cancer (Caco-2) cell lines. Compounds that showed activity in the cell-cycle assay were further evaluated in cell viability assays using PC3 and MCF-7 cells.
An improved synthesis of 5′-fluoro-5′-deoxyadenosines
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BMCL.2005.05.029
Abstract: Synthesis of 5'-fluoro-5'-deoxyadenosine (5'-FDA) and structurally similar compounds is generally a poor yielding process. This is attributed to the instability of the selected synthetic intermediates. Herein, we report a general synthesis of 5'-fluoro-5'-deoxy-N6-substituted adenosines including a high yielding access to 5'-FDA.
Identification of the Binding Site of Apical Membrane Antigen 1 (AMA1) Inhibitors Using a Paramagnetic Probe.
Publisher: Wiley
Date: 13-02-2019
Abstract: Apical membrane antigen 1 (AMA1) is essential for the invasion of host cells by malaria parasites. Several small-molecule ligands have been shown to bind to a conserved hydrophobic cleft in Plasmodium falciparum AMA1. However, a lack of detailed structural information on the binding pose of these molecules has hindered their further optimisation as inhibitors. We have developed a spin-labelled peptide based on RON2, the native binding partner of AMA1, to probe the binding sites of compounds on PfAMA1. The crystal structure of this peptide bound to PfAMA1 shows that it binds at one end of the hydrophobic groove, leaving much of the binding site unoccupied and allowing fragment hits to bind without interference. In paramagnetic relaxation enhancement (PRE)-based NMR screening, the
7,8-Didehydro-4,5-epoxy-17-methylmorphinan-6-yl naphthalene-1-carboxylate
Publisher: International Union of Crystallography (IUCr)
Date: 08-11-2003
Polonovski-Type N-Demethylation of N-Methyl Alkaloids Using Substituted Ferrocene Redox Catalysts
Publisher: Georg Thieme Verlag KG
Date: 23-07-2012
Subtype-Selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A2A Receptor
Publisher: American Chemical Society (ACS)
Date: 30-12-2019
DOI: 10.1021/ACS.JMEDCHEM.9B01856
Abstract: Among class A G protein-coupled receptors (GPCR), the human adenosine A
The design and synthesis of novel adenosine agonists
Publisher: Elsevier BV
Date: 04-1996
6,7-Dimethyl-5-phenyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one
Publisher: International Union of Crystallography (IUCr)
Date: 23-03-2001
The Dopamine D<sub>2</sub> and Adenosine A<sub>2A</sub> Receptors: Past, Present and Future Trends for the Treatment of Parkinson’s Disease
Publisher: Bentham Science Publishers Ltd.
Date: 11-08-2014
DOI: 10.2174/1389200215666140217110716
Abstract: Herein, we present an overview of the historic development of drugs for the treatment of Parkinson's disease as well as prospective novel treatment forms based on targeting the dopamine and adenosine receptors. The review includes the development of levodopa, a precursor of the neurotransmitter dopamine, which to date is the most commonly prescribed and most effective drug for controlling the motor symptoms of Parkinson's disease, to more recent studies of the adenosine receptor a promising target for the treatment of Parkinson's disease due to its intrinsic neuroprotective nature. Ongoing and future drug-based research on the dopamine and adenosine receptors has the advantage of being guided by the improved understanding of receptor topography as well as their functional roles. Breakthroughs such as the first ligand-bound X-ray structure of a selective adenosine A2A receptor antagonist in complex with the adenosine A2A receptor, the discovery of the existence of dopamine D2 homodimers, dopamine D2- adenosine A2A heterodimers and higher order oligomers in addition to technological progress have changed the direction of research in academia and industry and form the pillars for novel and exciting discoveries in this field.
Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits
Publisher: American Chemical Society (ACS)
Date: 23-05-2013
DOI: 10.1021/CN400086M
NMR case study of ropinirole: Concentration-dependent effects of nonexchangeable proton resonances
Publisher: Wiley
Date: 07-08-2014
DOI: 10.1002/MRC.4114
SYNTHESIS OF 2-SUBSTITUTED PYRAZOLO[3,4-D]PYRIMIDINES
Publisher: CSIRO Publishing
Date: 1991
DOI: 10.1071/CH9911795
Abstract: The reaction of 1-acetyl-2-phenylhydrazine with ethoxymethylenemalononitrile yielded [(4-cyano-1-phenylpyrazol-3-yl)aminomethylene]propanedinitrile. Hydrolysis followed by annulation with methyl isocyanate provided a synthetic route to 2-phenylpyrazolo[3,4-d]pyrimidines.
N-Demethylation of N-methyl alkaloids with ferrocene
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.BMCL.2010.06.031
Abstract: Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.
Author response: Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
Publisher: eLife Sciences Publications, Ltd
Date: 25-07-2022
Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the μ-Opioid Receptor
Publisher: American Chemical Society (ACS)
Date: 16-12-2015
DOI: 10.1021/ACS.JMEDCHEM.5B01664
Abstract: Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on the design, synthesis, and pharmacological evaluation of fluorescent probes for the opioid receptors, for which relatively few non-peptidic fluorescent probes currently exist. The known μ-opioid receptor (MOR) partial agonist, buprenorphine, was structurally elaborated to include an amidoalkylamine linker moiety that was coupled with a range of fluorophores to afford new fluorescent probes. All compounds proved to be selective MOR antagonists. Confocal fluorescence microscopy studies revealed that the probe incorporating a sulfonated cyanine-5 fluorophore was the most appropriate for imaging studies. This ligand was subsequently employed in an automated fluorescence-based competition binding assay, allowing the pKi values of several well-known opioid ligands to be determined. Thus, this new probe will prove useful in future studies of MOR receptor pharmacology.
Transformation of Poorly Water-Soluble Drugs into Lipophilic Ionic Liquids Enhances Oral Drug Exposure from Lipid Based Formulations
Publisher: American Chemical Society (ACS)
Date: 05-05-2015
DOI: 10.1021/MP500790T
Abstract: Absorption after oral administration is a requirement for almost all drug products but is a challenge for drugs with intrinsically low water solubility. Here, the weakly basic, poorly water-soluble drugs (PWSDs) itraconazole, cinnarizine, and halofantrine were converted into lipophilic ionic liquids to facilitate incorporation into lipid-based formulations and integration into lipid absorption pathways. Ionic liquids were formed via metathesis reactions of the hydrochloride salt of the PWSDs with a range of lipophilic counterions. The resultant active pharmaceutical ingredient-ionic liquids (API-ILs) were liquids or low melting point solids and either completely miscible or highly soluble in lipid based, self-emulsifying drug delivery systems (SEDDS) comprising mixtures of long or medium chain glycerides, surfactants such as Kolliphor-EL and cosolvents such as ethanol. They also readily incorporated into the colloids formed in intestinal fluids during lipid digestion. Itraconazole docusate or cinnarizine decylsulfate API-ILs were subsequently dissolved in long chain lipid SEDDS at high concentration, administered to rats and in vivo exposure assessed. The data were compared to control formulations based on the same SEDDS formulations containing the same concentrations of drug as the free base, but in this case as a suspension (since the solubility of the free base in the SEDDS was much lower than the API-ILs). For itraconazole, comparison was also made to a physical mixture of itraconazole free base and sodium docusate in the same SEDDS formulation. For both drugs plasma exposure was significantly higher for the API-IL containing formulations (2-fold for cinnarizine and 20-fold for itraconazole), when compared to the suspension formulations (or the physical mixture in the case of itraconazole) at the same dose. The liquid SEDDS formulations, made possible by the use of the API-ILs, also provide advantages in dose uniformity, capsule filling, and stability compared to similar suspension formulations. The data suggest that the formation of lipophilic ionic liquids provides a means of increasing dissolved-drug loading in lipid based formulations and thereby promoting the exposure of poorly water-soluble drugs after oral administration.
Pyrazolo[3,4-d]pyrimidine analogues of isoguanine
Publisher: Elsevier BV
Date: 11-1991
New irreversible adenosine A1 antagonists based on FSCPX
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1016/S0960-894X(02)00639-X
Abstract: FSCPX (1) and its amide analogue (2) have been reported to exhibit potent and selective irreversible antagonism of the A(1) adenosine receptor (A(1)AR) when used in in vitro biological preparations. In order to obtain an irreversible A(1)AR antagonist with improved stability, analogues of FSCPX incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine pharmacophore by a ketone linkage were explored. Compounds 4a-c exhibited improved affinity for the A(1)AR and concentration-dependent irreversible binding to the A(1)AR.
Experimental investigation of boundary layer transition in flow past a bluff body
Publisher: IOP Publishing
Date: 11-04-2017
Two-pronged attack: Dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors
Publisher: American Chemical Society (ACS)
Date: 24-10-2014
DOI: 10.1021/JM501323A
Abstract: Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.
The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D 2 receptor
Publisher: Elsevier BV
Date: 02-2018
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