ORCID Profile
0000-0002-8229-6591
Current Organisations
Fundação Oswaldo Cruz
,
Federal University of Rondonia
,
Monash University
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Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: Wiley
Date: 2001
DOI: 10.1002/JLCR.450
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2020
DOI: 10.1158/1078-0432.CCR-19-2641
Abstract: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by β-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative β-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30 80–160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P & 0.01), and AP-1 (P & 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P & 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells. One week of β-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that β-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of β-blockade on cancer recurrence and survival. See related commentary by Blaes et al., p. 1781
Publisher: Springer Science and Business Media LLC
Date: 02-01-2020
DOI: 10.1186/S12936-019-3075-5
Abstract: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. S le analysis was conducted by LC–MS/MS. Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D 7.4 . In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Publisher: American Chemical Society (ACS)
Date: 21-03-2012
DOI: 10.1021/JM3001373
Abstract: A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.01183-15
Abstract: ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum , as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum ( C max ) of 5.9 μM by 6 h after oral administration, and unlike ELQ-300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures.
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
Publisher: Wiley
Date: 2003
DOI: 10.1002/BDD.351
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/NCOMMS15159
Abstract: K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro , is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Publisher: American Chemical Society (ACS)
Date: 21-03-2013
DOI: 10.1021/JM400009C
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1002/JPS.24412
Publisher: Frontiers Media SA
Date: 14-12-2020
Abstract: Inflammation has been proposed to play a causal role in chemobrain which—if true—would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.
Publisher: American Chemical Society (ACS)
Date: 22-10-2014
DOI: 10.1021/JM500942V
Publisher: Proceedings of the National Academy of Sciences
Date: 12-2014
Abstract: Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.
Publisher: American Society for Microbiology
Date: 06-2015
DOI: 10.1128/AAC.05139-14
Abstract: With the aim of improving the available drugs for the treatment of Chagas disease, in idual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in their in vitro activity against a panel of Trypanosoma cruzi strains in vivo efficacy in a murine model of Chagas disease in vitro toxicity and absorption, distribution, metabolism, and excretion characteristics and in vivo pharmacokinetic properties. There is unlikely to be any therapeutic benefit of an in idual nifurtimox enantiomer over the racemic mixture.
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/981923
Abstract: Crude venom of Bothrops jararacussu and isolated phospholipases A 2 (PLA 2 ) of this toxin (BthTX-I and BthTX-II) were chemically modified (alkylation) by p -bromophenacyl bromide (BPB) in order to study antibody production capacity in function of the structure-function relationship of these substances (crude venom and PLA 2 native and alkylated). BthTX-II showed enzymatic activity, while BthTX-I did not. Alkylation reduced BthTX-II activity by 50% while this process abolished the catalytic and myotoxic activities of BthTX-I, while reducing its edema-inducing activity by about 50%. Antibody production against the native and alkylated forms of BthTX-I and -II and the cross-reactivity of antibodies to native and alkylated toxins did not show any apparent differences and these observations were reinforced by surface plasmon resonance (SPR) data. Histopathological analysis of mouse gastrocnemius muscle sections after injection of PBS, BthTX-I, BthTX-II, or both myotoxins previously incubated with neutralizing antibody showed inhibition of the toxin-induced myotoxicity. These results reveal that the chemical modification of the phospholipases A 2 (PLA 2 ) diminished their toxicity but did not alter their antigenicity. This observation indicates that the modified PLA 2 may provide a biotechnological tool to attenuate the toxicity of the crude venom, by improving the production of antibodies and decreasing the local toxic effects of this poisonous substance in animals used to produce antivenom.
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.BMCL.2012.11.056
Abstract: A series of novel glycopyranosyl azides were synthesised wherein the carbohydrate moiety was peracylated with four acetyl, propionyl, butanoyl, pentanoyl (valeryl) or 3-methylbutanoyl (isovaleryl) ester linked groups. A panel of glycoconjugates was synthesised from these glycopyranosyl azides using copper-catalysed azide-alkyne cycloaddition. The in vitro metabolic stability, plasma stability and plasma protein binding was then measured to establish the impact of the different acyl group when presented on a common scaffold. The acetyl, propionyl and butanoyl esters exhibited metabolism consistent with esterase processing, and various mono-, di- and tri-acylated hydrolysis products as well as the fully hydrolysed compound were detected. In contrast, the pentanoyl and 3-methylbutanoyl esters were stable.
Publisher: American Chemical Society (ACS)
Date: 12-05-2011
DOI: 10.1021/JM200265B
Publisher: American Society for Microbiology
Date: 08-2014
DOI: 10.1128/AAC.02754-13
Abstract: This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole-treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.
Publisher: American Chemical Society (ACS)
Date: 04-12-2013
DOI: 10.1021/JM401610C
Publisher: Elsevier BV
Date: 02-2018
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 22-06-2023
Publisher: American Chemical Society (ACS)
Date: 20-06-2012
DOI: 10.1021/JM3002795
Abstract: A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).
Publisher: Bentham Science Publishers Ltd.
Date: 10-2006
DOI: 10.2174/138920006778520589
Abstract: The vectorial movement of glucuronide conjugates from blood into bile can be an important elimination route for many drug metabolites, however the intrinsic hydrophilicity of those conjugates may conceptually act to reduce the overall efficiency of that process by limiting the flux of such conjugates across the sinusoidal membrane domain of hepatocytes. In this investigation, the hepatic disposition of the diastereomeric glucuronides of (R)- and (S)-2-phenylpropionic acid (a model "profen" compound) have been studied using the isolated perfused rat liver to establish whether a permeability barrier at the sinusoidal membrane domain (demonstrated previously for those conjugates) is of a sufficient magnitude to impact on the overall biliary excretion of these conjugates. Livers were perfused (30 mL/min) with perfusate containing either (R)-PPA, (S)-PPA, (R)-PPA-Glucuronide or (S)-PPA-Glucuronide in order to determine the dispositional profile of each glucuronide administered to the liver as both a preformed and an hepatically-generated metabolite. Once an apparent steady-state condition had been reached, infusion of test compound was ceased in order to establish the kinetics of the hepatic washout. The extent of biliary excretion of each glucuronide was dependent upon whether the glucuronide was presented to the liver as a preformed or hepatically-generated metabolite, and those differences, when analysed using a physiologically-based pharmacokinetic model, were consistent with the sinusoidal membrane acting as a barrier to the cellular entry of the glucuronides. Furthermore, that barrier was more pronounced for (R)-PPAG than it was for (S)-PPAG, suggesting that the hepatocellular uptake of the two diastereomers is stereoselective.
Publisher: American Chemical Society (ACS)
Date: 16-06-2011
DOI: 10.1021/JM200227R
Abstract: A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity and cytotoxicity following hits identified from screening commercially available compound collections. The most active of these, TDR86919 (4c), showed improved in vitro activity vs the drug-resistant K1 strain of Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM) potency was retained against a range of drug-sensitive and drug-resistant strains, with negligible cytotoxicity against the mammalian (L-6) cell line (selectivity index of >600). 4c and several close analogues (as HCl or mesylate salts) showed significant efficacy in P. berghei infected mice following both intraperitoneal (ip) and oral (po) administration, with >90% inhibition of parasitemia, accompanied by an increase in the mean survival time (MSD). The pyrido[1,2-a]benzimidazoles appeared to be relatively slow acting in vivo compared to chloroquine, and metabolic stability of the alkylamino side chain was identified as a key issue in influencing in vivo activity.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2011
Publisher: American Chemical Society (ACS)
Date: 05-03-2020
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.JCHROMB.2009.07.015
Abstract: OZ277 is a synthetic 1,2,4-trioxolane antimalarial currently being evaluated in clinical trails. Biotransformation of OZ277 in rats results in the generation of metabolites with large differences in polarity which complicates the development of a method for the simultaneous analysis of all species. A simple, sensitive and selective hydrophilic interaction liquid chromatography-mass spectroscopy (HILIC/MS) method for simultaneous determination of OZ277 and its major metabolites in rat plasma was developed and validated. The method involves protein precipitation with acetonitrile followed by separation on a Waters Atlantis HILIC Silica column using gradient elution. The analytes were monitored using a positive electrospray ionization interface in selected ion monitoring mode. The calibration range for all of the analytes was 5-10,000ng/mL and the lower limit of quantitation was 5ng/mL using a 50microL rat plasma s le. The inter- and intra-day accuracy and precision was within 12%. The recovery of all analytes from rat plasma over a wide concentration range was 90% or greater. The method has been successfully used for quantifying OZ277 and its metabolites in plasma following intravenous administration to rats.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
Publisher: Springer Science and Business Media LLC
Date: 2003
Abstract: To examine whether the small quantities of lipid present in unit-dose microemulsion formulations comprising medium- (C8-10) or long-chain (C18) glyceride lipids can stimulate the intestinal lymphatic transport of halofantrine (Hf), a model lymphatically transported drug. Hf (50 mg) was administered to thoracic lymph duct- and cephalic vein-cannulated fasted greyhound dogs. Drug was formulated as a single soft gelatin capsule containing approximately 1 g of a microemulsion preconcentrate based on either medium- or long-chain glycerides. Thoracic lymph was collected, and systemic plasma s les taken over 10 h postdose. The extent of lymphatic transport of Hf after administration of the long-chain lipid formulation was high (28.3% of dose), and significantly higher than that seen after administration of the medium-chain formulation (5.0% of dose). Plasma levels of Hf were not significantly different across the two formulations when assessed by AUC0-10h. This is the first study to demonstrate that the small amounts of lipid present within a single lipid-based dose form can support substantial intestinal lymphatic transport in the fasted state. Furthermore, microemulsions based on long-chain glycerides appear to be more effective with respect to lymphatic transport than the equivalent medium-chain formulation.
Publisher: American Chemical Society (ACS)
Date: 03-02-2010
DOI: 10.1021/JM901449M
Abstract: A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(1-->2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.
Publisher: Hindawi Limited
Date: 19-07-2022
DOI: 10.1155/2022/2748962
Abstract: In order to address the global antivenom crisis, novel antivenoms need to present high therapeutic efficacy, broad neutralization ability against systemic and local damage, sufficient safety, and cost-effectiveness. Due to biological characteristics of camelid single-domain antibodies (VHH) such as high affinity, their ability to penetrate dense tissues, and facility for genetic manipulation, their application in antivenoms has expanded considerably. VHHs that are active against the metalloprotease BjussuMP-II from the snake Bothrops jararacussu were selected. After isolation of BjussuMP-II, a camelid was immunized with the purified toxin in order to construct the recombinant phage library. Following a round of biopanning, 52% of the selected clones were able to recognize BjussuMP-II in an ELISA assay. After sequencing, seven sequence profiles were identified. One selected clone (VHH61) showed cross-reactivity to B. brazili venom, but did not recognize the Crotalus and Lachesis genera, indicating specificity for the Bothrops genus. Through in vitro tests, the capacity to neutralize the toxicity triggered by BjussuMP-II was observed. Circular dichroism spectroscopy indicated a robust secondary structure for VHH61, and the calculated melting temperature ( T M ) for the clone was 56.4°C. In silico analysis, through molecular docking of anti-BjussuMP-II VHHs with metalloprotease, revealed their potential interaction with amino acids present in regions critical for the toxin’s conformation and stability. The findings suggest that anti-BjussuMP-II VHHs may be beneficial in the development of next-generation antivenoms.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 13-06-2003
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMCL.2009.08.071
Abstract: A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2017
DOI: 10.1186/S40478-017-0456-2
Abstract: Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology . In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.
Publisher: American Society for Microbiology
Date: 09-2012
DOI: 10.1128/AAC.06244-11
Abstract: Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi , remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14α-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti- T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds.
Publisher: American Chemical Society (ACS)
Date: 04-10-2016
Publisher: Proceedings of the National Academy of Sciences
Date: 10-2015
Publisher: American Chemical Society (ACS)
Date: 20-04-2021
Publisher: American Chemical Society (ACS)
Date: 06-04-2020
Publisher: Springer Science and Business Media LLC
Date: 12-03-2009
DOI: 10.1007/S11095-009-9860-Z
Abstract: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first ex les of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2018
Publisher: Oxford University Press (OUP)
Date: 10-2003
Abstract: Foods and complementary medicines contain phytoestrogenic isoflavones such as genistein, which undergo hepatic glucuronidation and excretion into bile and can potentially interfere with the hepatic elimination of other compounds. To investigate this potential, livers from Sprague-Dawley rats were perfused in single-pass mode with preformed gemfibrozil 1-O-acyl glucuronide (GG) (1 μM, n = 12) for 60 min followed by a 30-min washout phase, or with gemfibrozil (1 μM n = 10) for 120 min. Half of each group of livers were co-perfused with genistein (10 μM) throughout the experiment. Perfusate and bile were analyzed for GG and gemfibrozil by HPLC. Co-perfusion with genistein significantly (P & 0.05) decreased the biliary extraction ratio of preformed GG from a mean of 0.82 to 0.65 and the first-order rate constant for transport of GG into bile from 0.054 + 0.010 to 0.032 + 0.008 min−1, but increased the first-order rate constant for sinusoidal efflux of GG from 0.128 + 0.023 to 0.227 + 0.078 min−1. Co-perfusion with genistein also significantly decreased the biliary extraction ratio of hepatically generated GG from 0.95 + 0.01 to 0.83 + 0.05. The findings confirm that genistein increases the potential for hepatic and systemic exposure to hepatically generated glucuronides, which may be important for patients on conventional drugs who consume isoflavones.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1002/JPS.24312
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2013
DOI: 10.1126/SCITRANSLMED.3005029
Abstract: ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1186/S12936-021-03617-1
Abstract: The ongoing global malaria eradication c aign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.
Publisher: American Chemical Society (ACS)
Date: 15-08-2018
Publisher: American Chemical Society (ACS)
Date: 18-01-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01586
Abstract: Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pK
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-04-2017
DOI: 10.1126/SCITRANSLMED.AAD9735
Abstract: MMV390048, a member of a new class of inhibitors of the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.
Publisher: Informa UK Limited
Date: 11-2013
DOI: 10.2147/DDDT.S51298
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.
Publisher: Elsevier BV
Date: 08-2014
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:JOPA.0000029486.60317.25
Abstract: Numerous studies have previously been conducted with the impulse-response isolated perfused rat liver (IR-IPRL) to establish the role of both physiological and physicochemical factors in determining solutes' pattern of hepatic disposition, however the impact of optical isomerism on hepatic disposition has hardly been studied using this methodology. In this study, the IR-IPRL was used to assess the extent of stereoselectivity exhibited by the kinetic processes involved in the hepatic disposition of the diastereomeric acyl glucuronides of (R)- and (S)-2-phenylpropionic acid (i.e. (R)- and (S)-PPAG). Moment and model-dependent (distributed model and axial dispersion model) analyses were conducted of the hepatic outflow profiles generated upon bolus administration of (R)-(14)C-PPAG or (S)-(14)C-PPAG and 3H-Sucrose (used as a marker of the hepatic vascular space) into the portal inflow of isolated perfused livers of male Sprague-Dawley rats (n = 4). Significant differences between (R)- and (S)-PPAG were apparent in the pharmacokinetic parameters defining the total hepatic disposition of the two diastereomers, the most marked being the hepatic availabilities, where the value for (S)-PPAG (0.721 +/- 0.059) was significantly lower than that of (R)-PPAG (0.909 +/- 0.042). The distributed and axial dispersion model analyses suggested that the more extensive hepatic extraction of (S)-PPAG was (at least in part) due to the higher sinusoidal membrane permeability-surface area product (PS UPT) of the diastereomer, and this has been considered in light of the emerging evidence regarding the role of hepatocellular membrane transport mechanisms. Furthermore, given the potential immunogenicity of acyl glucuronides (through covalent binding to plasma and intracellular proteins), the results of this study suggest that diastereomeric glucuronides may exhibit differing toxicity due to differences in their access to intracellular proteins.
Publisher: Elsevier BV
Date: 2022
Publisher: Proceedings of the National Academy of Sciences
Date: 07-02-2011
Abstract: Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei -infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2009
DOI: 10.1158/1535-7163.MCT-09-0076
Abstract: CYT997 is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 blocks the cell cycle at the G2-M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 possesses a useful combination of pharmacologic and pharmacokinetic properties and has considerable potential as a novel anticancer agent. [Mol Cancer Ther 2009 (11):3036–45]
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.IJBIOMAC.2017.04.013
Abstract: Snake venoms contain various proteins, especially phospholipases A
Publisher: American Chemical Society (ACS)
Date: 18-03-2009
DOI: 10.1021/JM801343R
Publisher: American Chemical Society (ACS)
Date: 10-06-2020
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.EJMECH.2021.113822
Abstract: MER tyrosine kinase (MERTK) upregulation is associated with M2 polarization of microglia, which plays a vital role in neuroregeneration following damage induced by neuroinflammatory diseases such as multiple sclerosis (MS). Therefore, a radiotracer specific for MERTK could be of great utility in the clinical management of MS, for the detection and differentiation of neuroregenerative and neurodegenerative processes. This study aimed to develop an [
Publisher: Elsevier BV
Date: 04-2021
Publisher: Bentham Science Publishers Ltd.
Date: 10-2005
DOI: 10.2174/138920005774330611
Abstract: The present study was designed to investigate the hepatic disposition of the prodrug AM365 and the generated antiviral guanosine analogue, AM188 in the isolated perfused rat liver (IPL). The livers of rats (n=12) were isolated and perfused with Krebs-Henseleit pH 7.4 buffer to which AM365 was added as a bolus to achieve an initial perfusate concentration of 22.4 micromol/L. During the 120-min period after administration of AM365, bile was collected in 10-min intervals and perfusate was collected at the mid-point of these intervals. Concentrations of AM365 and AM188 in perfusate and bile were quantified by HPLC. Following administration of AM365, its concentration in perfusate declined and the concentration of AM188 increased the sum of the molar concentrations remained constant. The clearance and hepatic extraction ratio of AM365 were 3.3+/-2.4 mL/min and 0.110+/-0.079, respectively. The cumulative amount of AM365 excreted in bile during the 120-min perfusion period was approximately 0.21% of the bolus dose, and 0.36% of the total amount of AM365 cleared by the liver during the period. The cumulative amount of AM188 excreted in bile was about 0.48% of the total amount of AM188 formed during the perfusion period. In conclusion, AM365 was metabolised to AM188, which appeared to be the only metabolite and was not further biotransformed. The biliary excretion of AM365 and AM188 was negligible.
Publisher: American Chemical Society (ACS)
Date: 30-04-2021
Publisher: American Chemical Society (ACS)
Date: 14-07-2011
DOI: 10.1021/JM200592F
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 2003
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.BMC.2018.05.006
Abstract: A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.BMCL.2009.06.079
Abstract: CYT997 was discovered as a potent tubulin polymerization inhibitor possessing potent cytotoxic activity against a range of cancer cells. Details of SAR studies, pharmacokinetic investigations and synthesis of compounds leading to the discovery of CYT997 are reported.
Publisher: American Chemical Society (ACS)
Date: 24-03-2021
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.NEUROPHARM.2018.10.028
Abstract: The histamine H
Publisher: American Chemical Society (ACS)
Date: 02-03-2020
Publisher: Springer Science and Business Media LLC
Date: 17-10-2016
DOI: 10.1038/SREP35351
Abstract: The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5–8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.BMC.2013.01.050
Abstract: A scaffold hopping exercise undertaken to expand the structural ersity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days.
Publisher: American Chemical Society (ACS)
Date: 08-06-2021
Publisher: American Chemical Society (ACS)
Date: 28-11-2016
Publisher: IOP Publishing
Date: 11-04-2017
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.XPHS.2016.07.019
Abstract: Estimating uncertainty in the ratio of 2 measured variables can be achieved via 2 seemingly different approaches: by determining the variance of the first-order Taylor approximation to the ratio, or by the so-called "Propagation of Error" approach. This Lesson Learned shows that the 2 approaches are mathematically equivalent, and provides an ex le of the approach.
No related grants have been discovered for David Shackleford.