RESUMO
In recent years, some endogenous substrates of organic anion transporting polypeptide 1B (OATP1B) have been identified and characterized as potential biomarkers to assess OATP1B-mediated clinical drug-drug interactions (DDIs). However, quantitative determination of their selectivity to OATP1B is still limited. In this study, we developed a relative activity factor (RAF) method to determine the relative contribution of hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1, and sodium-taurocholate co-transporting polypeptide (NTCP) on hepatic uptake of several OATP1B biomarkers, including coproporphyrin I (CPI), coproporphyrin I CPIII, and sulfate conjugates of bile acids: glycochenodeoxycholic acid sulfate (GCDCA-S), glycodeoxycholic acid sulfate (GDCA-S), and taurochenodeoxycholic acid sulfate (TCDCA-S). RAF values for OATP1B1, OATP1B3, OATP2B1, and NTCP were determined in cryopreserved human hepatocytes and transporter transfected cells using pitavastatin, cholecystokinin, resveratrol-3-O-ß-D-glucuronide, and taurocholic acid (TCA) as reference compounds, respectively. OATP1B1-specific pitavastatin uptake in hepatocytes was measured in the absence and presence of 1 µM estropipate, whereas NTCP-specific TCA uptake was measured in the presence of 10 µM rifampin. Our studies suggested that CPI was a more selective biomarker for OATP1B1 than CPIII, whereas GCDCA-S and TCDCA-S were more selective to OATP1B3. OATP1B1 and OATP1B3 equally contributed to hepatic uptake of GDCA-S. The mechanistic static model, incorporating the fraction transported of CPI/III estimated by RAF and in vivo elimination data, predicted several perpetrator interactions with CPI/III. Overall, RAF method combined with pharmacogenomic and DDI studies is a useful tool to determine the selectivity of transporter biomarkers and facilitate the selection of appropriate biomarkers for DDI evaluation. SIGNIFICANCE STATEMENT: The authors developed a new relative activity factor (RAF) method to quantify the contribution of hepatic uptake transporters organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, and sodium taurocholate co-transporting polypeptide (NTCP) on several OATP1B biomarkers and evaluated their predictive value on drug-drug interactions (DDI). These studies suggest that the RAF method is a useful tool to determine the selectivity of transporter biomarkers. This method combined with pharmacogenomic and DDI studies will mechanistically facilitate the selection of appropriate biomarkers for DDI prediction.
Assuntos
Transportadores de Ânions Orgânicos , Humanos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Transportador 1 de Ânion Orgânico Específico do Fígado , Hepatócitos , Proteínas de Membrana Transportadoras , Biomarcadores , Interações MedicamentosasRESUMO
The multidrug resistance protein 1 (MDR1) P-glycoprotein (P-gp) is a clinically important transporter. In vitro P-gp inhibition assays have been routinely conducted to predict the potential for clinical drug-drug interactions (DDIs) mediated by P-gp. However, high interlaboratory and intersystem variability of P-gp IC50 data limits accurate prediction of DDIs using static models and decision criteria recommended by regulatory agencies. In this study, we calibrated two in vitro P-gp inhibition models: vesicular uptake of N-methyl-quinidine (NMQ) in MDR1 vesicles and bidirectional transport (BDT) of digoxin in Lilly Laboratories Cell Porcine Kidney 1 cells overexpressing MDR1 (LLC-MDR1) using a total of 48 P-gp inhibitor and noninhibitor drugs and digoxin DDI data from 70 clinical studies. Refined thresholds were derived using receiver operating characteristic analysis, and their predictive performance was compared with the decision frameworks proposed by regulatory agencies and selected reference. Furthermore, the impact of various IC50 calculation methods and nonspecific binding of drugs on DDI prediction was evaluated. Our studies suggest that the concentration of inhibitor based on highest approved dose dissolved in 250 ml divided by IC50(I2/IC50) is sufficient to predict P-gp related intestinal DDIs. IC50 obtained from vesicular inhibition assay with a refined threshold of I2/IC50 ≥ 25.9 provides comparable predictive power over those measured by net secretory flux and efflux ratio in LLC-MDR1 cells. We therefore recommend vesicular P-gp inhibition as our preferred method given its simplicity, lower variability, higher assay throughput, and more direct estimation of in vitro kinetic parameters, rather than BDT assay. SIGNIFICANCE STATEMENT: This study has conducted comprehensive calibration of two in vitro P-gp inhibition models: uptake in MDR1 vesicles and bidirectional transport in LLC-MDR1 cell monolayers to predict DDIs. This study suggests that IC50s obtained from vesicular inhibition with a refined threshold of I2/IC50 ≥ 25.9 provide comparable predictive power over those in LLC-MDR1 cells. Therefore, vesicular P-gp inhibition is recommended as the preferred method given its simplicity, lower variability, higher assay throughput, and more direct estimation of in vitro kinetic parameters.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Digoxina , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico/fisiologia , Digoxina/metabolismo , Suínos , TranscitoseRESUMO
Hepatocellular accumulation of bile salts by inhibition of bile salt export pump (BSEP/ABCB11) may result in cholestasis and is one proposed mechanism of drug-induced liver injury (DILI). To understand the relationship between BSEP inhibition and DILI, we evaluated 64 DILI-positive and 57 DILI-negative compounds in BSEP, multidrug resistance protein (MRP) 2, MRP3, and MRP4 vesicular inhibition assays. An empirical cutoff (5 µM) for BSEP inhibition was established based on a relationship between BSEP IC50 values and the calculated maximal unbound concentration at the inlet of the human liver (fu*Iin,max, assay specificity = 98%). Including inhibition of MRP2-4 did not increase DILI predictivity. To further understand the potential to inhibit bile salt transport, a selected subset of 30 compounds were tested for inhibition of taurocholate (TCA) transport in a long-term human hepatocyte micropatterned co-culture (MPCC) system. The resulting IC50 for TCA in vitro biliary clearance and biliary excretion index (BEI) in MPCCs were compared with the compound's fu*Iin,max to assess potential risk for bile salt transport perturbation. The data show high specificity (89%). Nine out of 15 compounds showed an IC50 value in the BSEP vesicular assay of <5µM, but the BEI IC50 was more than 10-fold the fu*Iin,max, suggesting that inhibition of BSEP in vivo is unlikely. The data indicate that although BSEP inhibition measured in membrane vesicles correlates with DILI risk, that measurement of this assay activity is insufficient. A two-tiered strategy incorporating MPCCs is presented to reduce BSEP inhibition potential and improve DILI risk. SIGNIFICANCE STATEMENT: This work describes a two-tiered in vitro approach to de-risk compounds for potential bile salt export pump inhibition liabilities in drug discovery utilizing membrane vesicles and a long-term human hepatocyte micropatterned co-culture system. Cutoffs to maximize specificity were established based on in vitro data from a set of 121 DILI-positive and -negative compounds and associated calculated maximal unbound concentration at the inlet of the human liver based on the highest clinical dose.
Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Descoberta de Drogas/métodos , Ácido Taurocólico/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Técnicas de Cocultura , Avaliação Pré-Clínica de Medicamentos/métodos , Hepatócitos , Humanos , Concentração Inibidora 50 , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismoRESUMO
Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with â¼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 µM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.
Assuntos
Interações Medicamentosas/fisiologia , Piridonas/metabolismo , Triazóis/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Citocromo P-450 CYP3A/metabolismo , Cães , Células HEK293 , Hepatócitos/metabolismo , Humanos , Cinética , Células Madin Darby de Rim Canino , Proteínas de Membrana Transportadoras/metabolismoRESUMO
OBJECTIVES: To identify the transporters involved in renal elimination of relebactam, and to assess the potential of relebactam as a perpetrator or victim of drug-drug interactions (DDIs) for major drug transporters. METHODS: A series of bidirectional transport, uptake and inhibition studies were conducted in vitro using transfected cell lines and membrane vesicles. The inhibitory effects of relebactam on major drug transporters, as well as the inhibitory effects of commonly used antibiotics/antifungals on organic anion transporter (OAT) 3-mediated uptake of relebactam, were assessed. RESULTS: Relebactam was shown to be a substrate of OAT3, OAT4, and multidrug and toxin extrusion (MATE) proteins MATE1 and MATE2K. Relebactam did not show profound inhibition across a panel of transporters, including organic anion-transporting polypeptides 1B1 and 1B3, OAT1, OAT3, organic cation transporter 2, MATE1, MATE2K, breast cancer resistance protein, multidrug resistance protein 1 and the bile salt export pump. Among the antibiotics/antifungals assessed for potential DDIs, probenecid demonstrated the most potent in vitro inhibition of relebactam uptake; however, such in vitro data did not translate into clinically relevant DDIs, suggesting that relebactam can be co-administered with OAT inhibitors, such as probenecid. CONCLUSIONS: Overall, relebactam has low potential to be a victim or perpetrator of DDIs with major drug transporters.
Assuntos
Compostos Azabicíclicos/farmacocinética , Transporte Biológico , Rim/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Inibidores de beta-Lactamases/farmacocinética , Animais , Linhagem Celular , Vesículas Extracelulares , Humanos , Modelos BiológicosRESUMO
Raltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series of in vitro experiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 µM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 µM and 18.8 µM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 µM) and MATE2-K (29% inhibition at 100 µM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Pirrolidinonas/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Animais , Cães , Interações Medicamentosas , Humanos , Técnicas In Vitro , Transportador 1 de Ânion Orgânico Específico do Fígado , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/efeitos dos fármacos , Proteína 1 Transportadora de Ânions Orgânicos/efeitos dos fármacos , Transportadores de Ânions Orgânicos/efeitos dos fármacos , Transportadores de Ânions Orgânicos Sódio-Independentes/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/efeitos dos fármacos , Transportador 1 de Cátions Orgânicos/efeitos dos fármacos , Transportador 2 de Cátion Orgânico , Raltegravir Potássico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de SolutoRESUMO
AIMS: Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS: The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS: Rifampicin markedly increased exposures of both statins, with greater differential increases after POâ vs.â IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS: The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.
Assuntos
Fluorbenzenos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Pirimidinas/farmacocinética , Quinolinas/farmacocinética , Rifampina/farmacologia , Sulfonamidas/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Rifampina/administração & dosagem , Rosuvastatina Cálcica , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Adulto JovemRESUMO
The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.
Assuntos
Anti-Hipertensivos/química , Desenho de Fármacos , Isoxazóis/química , Isoxazóis/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Domínio Catalítico , Ativação Enzimática/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins. These models successfully predicted a total of 46 statin DDIs, including above DAA drugs and their fix-dose combination regimens. Predicted plasma area under curve ratio (AUCR) with and without perpetrator drugs was within ~ 2-fold of observed values. In contrast, simplified static R-value model resulted in increased false negative and false positive predictions when different prediction cut-off values were applied. Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.
Assuntos
Hepatite C Crônica , Inibidores de Hidroximetilglutaril-CoA Redutases , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antivirais , Interações Medicamentosas , Hepacivirus/metabolismo , Hepatite C Crônica/tratamento farmacológico , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Neoplasias/metabolismoRESUMO
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptores de Dopamina D2/agonistas , Amidas/química , Animais , Indóis/química , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , RatosRESUMO
The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.
Assuntos
Anti-Hipertensivos/química , Piperidinas/química , Inibidores de Proteases/química , Renina/antagonistas & inibidores , Compostos de Espiro/química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Desenho de Fármacos , Humanos , Hipertensão/tratamento farmacológico , Macaca mulatta , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Animais , Carbolinas/química , Humanos , Indóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Permeabilidade da Membrana Celular/efeitos dos fármacos , Piperidinas/farmacologia , Renina/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Camundongos Knockout , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Renina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
Assuntos
Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Administração Oral , Animais , Domínio Catalítico , Simulação por Computador , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.
Assuntos
Desenho de Fármacos , Hipertensão/tratamento farmacológico , Piperidinas/síntese química , Piridonas/síntese química , Renina/antagonistas & inibidores , Animais , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/uso terapêutico , Piridonas/química , Piridonas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.
Assuntos
Álcoois/síntese química , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/uso terapêutico , Desenho de Fármacos , Hipertensão/tratamento farmacológico , Piperidinas/síntese química , Renina/antagonistas & inibidores , Álcoois/química , Álcoois/uso terapêutico , Animais , Anti-Hipertensivos/química , Estrutura Molecular , Piperidinas/química , Piperidinas/uso terapêutico , Ratos , Renina/química , Relação Estrutura-AtividadeRESUMO
In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.
Assuntos
Carbolinas/química , Pneumopatias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Humanos , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase-mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.
Assuntos
Desoxiadenosinas/metabolismo , Interações Medicamentosas , Preparações Farmacêuticas/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Animais , Transporte Biológico , Sistema Enzimático do Citocromo P-450/metabolismo , Desoxiadenosinas/sangue , Cães , Infecções por HIV/tratamento farmacológico , Humanos , Técnicas In Vitro , Células Madin Darby de Rim Canino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Transportadores de Ânions Orgânicos/metabolismo , CoelhosRESUMO
Time-dependent inhibitors of CYPs have the potential to perpetrate drug-drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Inibidores Enzimáticos/farmacologia , Propionatos/química , Renina/antagonistas & inibidores , Amidas/química , Citocromo P-450 CYP3A , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologiaRESUMO
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.