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1.
Drug Metab Dispos ; 47(11): 1352-1360, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31427432

RESUMO

Recent pharmacogenetic evidence indicates that hepatic organic cation transporter (OCT) 1 can serve as the locus of drug-drug interactions (DDIs) with significant pharmacokinetic and pharmacodynamic consequences. We examined the impact of preincubation on the extent of OCT1 inhibition in transfected human embryonic kidney 293 (HEK293) cells. Following 30-minute preincubation with an inhibitor, approximately 50-fold higher inhibition potency was observed for cyclosporine A (CsA) against OCT1-mediated uptake of metformin compared with coincubation, with IC50 values of 0.43 ± 0.12 and 21.6 ± 4.5 µM, respectively. By comparison, only small shifts (≤2-fold) in preincubation IC50 versus coincubation were observed for quinidine, pyrimethamine, ritonavir, and trimethoprim. The shift in CsA OCT1 IC50 was substrate dependent since it ranged from >1.2- to 50.2-fold using different experimental substrates. The inhibition potential of CsA toward OCT1 was confirmed by fenoterol hepatocyte uptake experiment. Furthermore, no shift in CsA IC50 was observed with HEK293 cells transfected with OCT2 and organic anion transporter (OAT) 1 and OAT3. Short exposure (30 minutes) to 10 µM CsA produced long-lasting inhibition (at least 120 minutes) of the OCT1-mediated uptake of metformin in OCT1-HEK293 cells, which was likely attributable to the retention of CsA in the cells, as shown by the fact that inhibitory cellular concentrations of CsA were maintained long after the removal of the compound from the incubation buffer. The potent and persistent inhibitory effect after exposure to CsA warrants careful consideration in the design and interpretation of clinical OCT1 DDI studies. SIGNIFICANCE STATEMENT: Preincubation of OATP1B1 and OATP1B3 with their inhibitor may result in the enhancement of the inhibitory potency in a cell-based assay. However, limited data are available on potentiation of OCT1 inhibition by preincubation, which is a clinically relevant drug transporter. For the first time, we observed a 50-fold increase in CsA inhibitory potency against OCT1-mediated transport of metformin following a preincubation step. The CsA preincubation effect on OCT1 inhibition is substrate dependent. Moreover, the inhibition potential of CsA toward OCT1 is confirmed by hepatocyte uptake experiment. This study delivers clear evidences about the potent and persistent inhibitory effect on OCT1 after exposure to CsA. Further studies are needed to assess the effect of CsA on OCT1 drug substrates in vivo.

2.
Mol Pharm ; 16(9): 4065-4076, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31335150

RESUMO

Following oral administration, dabigatran etexilate (DABE) is rapidly hydrolyzed to its active form, dabigatran. DABE, but not dabigatran, presents as a P-glycoprotein (P-gp) substrate and has increasingly been used as a probe drug. Therefore, although dosed as DABE, a P-gp drug-drug interaction (DDI) is reported as a dabigatran plasma concentration ratio (perpetrator versus placebo). Because the majority of a DABE dose (80 to 85%) is recovered in urine as unchanged dabigatran (renal active secretion is ∼25% of total clearance), dabigatran was evaluated in vitro as a substrate of various human renal transporters. Active (pyrimethamine-sensitive) dabigatran uptake was observed with human embryonic kidney (HEK) 293 cells expressing multidrug and toxin extrusion protein 1 (MATE1) and 2K (MATE2K), with Michaelis-Menten constant (Km) values of 4.0 and 8.0 µM, respectively. By comparison, no uptake of 2 µM dabigatran (versus mock-transfected HEK293 cells) was evident with HEK293 cells transfected with organic cation transporters (OCT1 and OCT2) and organic anion transporters (OAT1, 2, 3, and 4). The efflux ratios of dabigatran across P-gp- and BCRP (breast cancer resistance protein)-MDCK (Madin-Darby canine kidney) cell monolayers were 1.5 and 2.0 (versus mock-MDCK cell monolayers), suggesting dabigatran is a relatively poor P-gp and BCRP substrate. Three of five drugs (verapamil, ketoconazole, and quinidine) known to interact clinically with dabigatran, as P-gp inhibitors, presented as MATE inhibitors in vitro (IC50 = 1.0 to 25.2 µM). Taken together, although no basolateral transporter was identified for dabigatran, the results suggest that apical MATE1 and MATE2K could play an important role in its renal clearance. MATE-mediated renal secretion of dabigatran needs to be considered when interpreting the results of P-gp DDI studies following DABE administration.

3.
Mol Pharm ; 16(6): 2342-2353, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31039308

RESUMO

Identification of a selective inhibitor of organic anion transporting polypeptide (OATP) 1B1 is critical in order to determine the contribution of OATP1B1-mediated uptake of investigational drugs into human hepatocytes for successful in vitro-to-in vivo extrapolation (IVIVE) of hepatic uptake and drug-drug interaction (DDI). The following study examined the inhibitory effects of estropipate (EPP) on major sinusoidal drug uptake transporters and explored its utility regarding IVIVE of statin hepatic disposition. EPP and its free-base form (i.e., estrone sulfate) showed a potent and high degree of selectivity in inhibiting the OATP1B1-mediated transport of rosuvastatin with an IC50 value averaging 0.05 ± 0.01 and 0.12 ± 0.07 µM for human and cynomolgus monkey OATP1B1 (hOATP1B1 and cOATP1B1), respectively, whereas weak inhibition was observed for human and monkey OATP1B3, OATP2B1, sodium-taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2, and organic cation transporter 1 with IC50 values ranging from 8.6 to 64.0 µM. EPP, together with rifamycin SV, was subsequently used to determine the fractions of hepatic uptake clearance ( fT) of statins, including rosuvastatin, pitavastatin, and dehydropravastatin, which are reported to be mediated by OATP1B1, OATP1B3, OATP2B1, and NTCP. Finally, the magnitudes of in vivo inhibition of rosuvastatin clearance caused by EPP and rifampin in cynomolgus monkeys were predicted by using individual transporter IC50 and fT (AUC fold change 1.28 vs 1.21, 2.71 vs 1.75, and 3.35 vs 2.83, respectively). These results suggest that EPP is an appropriate OATP1B1-selective inhibitor to establish the relative contribution of OATP1B1 to hepatic uptake in vitro and to discern the role of OATP1B1 in hepatic disposition in vivo.

4.
Curr Drug Metab ; 20(1): 2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30887914
5.
Xenobiotica ; 49(12): 1403-1413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30747549

RESUMO

1. Terbinafine (TBF), a common antifungal agent, has been associated with rare incidences of hepatotoxicity. It is hypothesized that bioactivation of TBF to reactive intermediates and subsequent binding to critical cellular proteins may contribute to this toxicity. In the present study, we have characterized the bioactivation pathways of TBF extensively in human, mouse, monkey, dog and rat liver microsomes and hepatocytes. 2. A total of twenty glutathione conjugates of TBF were identified in hepatocytes; thirteen of these conjugates were also detected in liver microsomes. To the best of our knowledge, only two of these conjugates have been reported previously. The conjugates were categorized into three groups based on their mechanism of formation: (a) alkene/alkyne oxidation followed by glutathione conjugation, with or without N-demethylation, (b) arene oxidation followed by glutathione conjugation, with or without N-demethylation, and (c) N-dealkylation followed by glutathione conjugation of the allylic aldehyde, alcohol and acid intermediates. 3. Differences were observed across species in the contributions of these pathways toward overall metabolic turnover. We conclude that, in addition to the glutathione conjugates known to form by Michael addition to the allylic aldehyde, there are other pathways involving the formation of arene oxides and alkene/alkyne epoxides that may be relevant to the discussion of TBF-mediated idiosyncratic drug reactions.

6.
ACS Med Chem Lett ; 9(5): 472-477, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795762

RESUMO

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

7.
Drug Metab Lett ; 11(2): 138-143, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29283075

RESUMO

BACKGROUND: The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition. OBJECTIVE: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., Bile Acid-CoA Synthetase (BACS) and bile acid-CoA: amino acid Nacetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model. RESULTS: In human hepatocytes, treatment with the FXR agonists GW4064 (1.0 µM) and WAY362450 (0.1 µM) did not significantly induce the mRNA expression of BACS and BAT genes. However, other target genes associated with FXR activation, such as Bile Salt Export Pump (BSEP), Short Heterodimer Partner (SHP), Multidrug Resistance-associated Protein 2 (MRP2) and Multidrug Resistance Protein 3 (MDR3), were upregulated. Interestingly, a follow up study conducted in rat hepatocytes indicated that GW4064 induced the BACS gene while WAY362450 induced the BAT gene, confirming literature results that these genes can be induced in rat. CONCLUSION: In conclusion, there appears to be some species differences in the activation of FXR target genes.


Assuntos
Aciltransferases/genética , Coenzima A Ligases/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Ativação Transcricional/efeitos dos fármacos , Aciltransferases/metabolismo , Animais , Azepinas/farmacologia , Células Cultivadas , Coenzima A Ligases/metabolismo , Hepatócitos , Humanos , Indóis/farmacologia , Isoxazóis/farmacologia , Cultura Primária de Células , RNA Mensageiro/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Especificidade da Espécie , Regulação para Cima
9.
J Pharmacol Exp Ther ; 363(3): 377-393, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28954811

RESUMO

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 µM) and had negligible activity in an assay panel containing 40 additional pharmacological targets. Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Organofosfatos/uso terapêutico , Piperidinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Pirrolidinonas/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Intravenosa , Regulação Alostérica , Animais , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Ondas Encefálicas/efeitos dos fármacos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Transtornos Dissociativos/induzido quimicamente , Macaca fascicularis , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Xenopus
10.
Drug Metab Dispos ; 45(10): 1049-1059, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28646080

RESUMO

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles.


Assuntos
Citocromo P-450 CYP2B6/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Regulação para Baixo/fisiologia , Interações de Medicamentos/fisiologia , Preparações Farmacêuticas/metabolismo , Indústria Farmacêutica/métodos , Humanos , Estados Unidos , United States Food and Drug Administration
11.
J Med Chem ; 60(10): 4369-4385, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28430437

RESUMO

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.


Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Benzofuranos/farmacologia , Benzofuranos/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Antivirais/química , Benzofuranos/química , Cães , Descoberta de Drogas , Haplorrinos , Hepatite C/virologia , Humanos , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
12.
Drug Metab Lett ; 10(4): 264-269, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27908259

RESUMO

BACKGROUND: Bilirubin is a toxic waste product of metabolism, eliminated mainly through UGT1A1 mediated conjugation to mono- and di-glucuronides. Due to the potentially low Km value of bilirubin glucuronidation, the quantitative sensitivity obtained with most UV/visible light detection methods are not sufficient to accurately calculate UGT1A1 enzyme kinetics at low bilirubin concentrations. In addition, bilirubin, as well as its metabolites, are unstable during sample preparation and bioanalysis. This necessitates the need for a rapid, sensitive and robust assay to measure bilirubin glucuronides. METHODS: A robust LC-MS/MS method was developed to measure low levels of bilirubin glucuronides accurately from in vitro incubations, as well as stabilizing the analytes during sample preparation and analysis. The metabolites were quantified using a qualitative/quantitative approach utilizing UV to MS correction, thereby eliminating the need for synthetic standards. RESULTS: The method was sensitive enough to quantify mono- and di-glucuronides as low as 3 nM from in vitro incubations, and kinetic data was determined for total glucuronide formation. The Km and Vmax values for total bilirubin glucuronide formations were determined to be 0.05 ± 0.01 µM and 181.9 ± 5.3 pmol/min/mg-protein, respectively, in human recombinant UGT1A1, and 0.23 ± 0.05 µM and 875 ± 45 pmol/min/mg protein in human liver microsomes (HLM). CONCLUSION: We have developed a sensitive LC-MS/MS based method for the quantitation of bilirubin and its glucuronides from in vitro incubations. This method was successfully utilized to determine bilirubin glucuronidation kinetics in HLM and human rUGT1A1.


Assuntos
Bilirrubina/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos/métodos , Glucuronosiltransferase/metabolismo , Espectrometria de Massas em Tandem/métodos , Bilirrubina/análise , Bilirrubina/metabolismo , Humanos , Cinética , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/metabolismo , Sensibilidade e Especificidade
13.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27564532

RESUMO

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).


Assuntos
Antivirais/química , Hepacivirus/efeitos dos fármacos , Isoquinolinas/uso terapêutico , Oligopeptídeos/química , Sulfonamidas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/farmacologia , Cães , Esquema de Medicação , Farmacorresistência Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Coelhos , Ratos Sprague-Dawley , Replicon , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
14.
Drug Metab Dispos ; 44(10): 1720-30, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27422672

RESUMO

Drug-drug interactions (DDIs) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. This work aimed to evaluate the potency of CYP2B6 versus CYP3A4 induction in vitro and from clinical studies and to assess the predictability of efavirenz versus bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDIs caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the relative induction score, net effect, and physiologically based pharmacokinetics SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results because of the lack of selectivity of these probes. Although in vitro-in vivo extrapolation for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the coinduction of CYP2B6 and CYP3A4, as well as the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fraction metabolized > 0.9) is needed to improve in vitro-in vivo extrapolation for characterizing the potential for CYP2B6-mediated DDIs. Alternative strategies and a framework for evaluating the CYP2B6 induction risk are proposed.


Assuntos
Indutores do Citocromo P-450 CYP2B6/farmacologia , Células Cultivadas , Interações de Medicamentos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos
15.
Drug Metab Dispos ; 44(8): 1399-423, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27052879

RESUMO

Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.


Assuntos
Descoberta de Drogas/normas , Indústria Farmacêutica/normas , Enzimas/metabolismo , Modelos Teóricos , Preparações Farmacêuticas/metabolismo , Animais , Biotransformação , Simulação por Computador , Árvores de Decisões , Descoberta de Drogas/métodos , Interações de Medicamentos , Humanos , Cinética , Preparações Farmacêuticas/química , Medição de Risco , Especificidade da Espécie , Especificidade por Substrato
16.
J Pharm Sci ; 104(9): 2813-23, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25631585

RESUMO

Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1.


Assuntos
Antivirais/farmacocinética , Hepacivirus/enzimologia , Isoquinolinas/farmacocinética , Inibidores de Proteases/farmacocinética , Sulfonamidas/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Bile/metabolismo , Disponibilidade Biológica , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Cães , Hepacivirus/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley
17.
ACS Med Chem Lett ; 5(7): 760-5, 2014 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25050161

RESUMO

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

18.
J Pharm Sci ; 103(6): 1891-902, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24700293

RESUMO

BMS-605339 is a potent HCV NS3 protease inhibitor that suppresses hepatitis C virus replication and was under investigation as an oral agent for the treatment of this disease. In vitro and in vivo studies were conducted in mouse, rat, dog, and monkey to characterize the pharmacokinetics and metabolism of this compound. BMS-605339 was predicted to be a moderate clearance compound in the human, based on human microsomal and hepatocyte data. Nearly all metabolism of BMS-605339 was oxidative; CYP3A4 is likely to play a key role in the metabolic clearance of this compound. Moderate to high Caco-2 permeability was observed for this compound, with the potential for P-glycoprotein involvement. The oral bioavailability of BMS-605339 was variable and dose dependent, suggesting low absorption, possibly because of transporter involvement. BMS-605339 possesses low intrinsic aqueous solubility and, in both rat and dog, administration of an aqueous suspension suggested that BMS-605339 absorption is likely solubility limited. Liver exposure of BMS-605339 was consistently higher than plasma exposure in all species tested (mouse, rat, and dog), indicating the potential for active uptake into hepatocytes. The overall preclinical pharmacokinetic profile supported the selection and development of BMS-605339 as a clinical candidate.


Assuntos
Antivirais/farmacocinética , Isoquinolinas/farmacocinética , Sulfonamidas/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Disponibilidade Biológica , Células CACO-2 , Cães , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley
19.
J Med Chem ; 57(5): 1730-52, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24564672

RESUMO

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/sangue , Antivirais/química , Cães , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Coelhos , Ratos , Sulfonamidas/sangue , Sulfonamidas/química
20.
J Med Chem ; 57(5): 1708-29, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24555570

RESUMO

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.


Assuntos
Antivirais/uso terapêutico , Descoberta de Drogas , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/química , Sulfonamidas/química
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