RESUMEN
1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption.
Asunto(s)
Metoprolol/metabolismo , Triazoles/metabolismo , Animales , Interacciones Farmacológicas/fisiología , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Masculino , Metoprolol/química , Metoprolol/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Triazoles/química , Triazoles/farmacologíaRESUMEN
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.
Asunto(s)
Antihipertensivos/química , Diseño de Fármacos , Isoxazoles/química , Isoxazoles/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Dominio Catalítico , Activación Enzimática/efectos de los fármacos , Humanos , Isoxazoles/farmacología , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antihipertensivos/química , Piperidinas/química , Inhibidores de Proteasas/química , Renina/antagonistas & inhibidores , Compuestos de Espiro/química , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Perros , Diseño de Fármacos , Humanos , Hipertensión/tratamiento farmacológico , Macaca mulatta , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Ratas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Permeabilidad de la Membrana Celular/efectos de los fármacos , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Transporte Biológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Ratas , Renina/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Alcoholes/síntesis química , Antihipertensivos/síntesis química , Antihipertensivos/uso terapéutico , Diseño de Fármacos , Hipertensión/tratamiento farmacológico , Piperidinas/síntesis química , Renina/antagonistas & inhibidores , Alcoholes/química , Alcoholes/uso terapéutico , Animales , Antihipertensivos/química , Estructura Molecular , Piperidinas/química , Piperidinas/uso terapéutico , Ratas , Renina/química , Relación Estructura-ActividadRESUMEN
Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
Asunto(s)
Profármacos/química , Antagonistas del Receptor Purinérgico P2/química , Receptores Purinérgicos P2/química , Disponibilidad Biológica , Humanos , Microsomas Hepáticos/metabolismo , Profármacos/síntesis química , Profármacos/farmacocinética , Unión Proteica , Antagonistas del Receptor Purinérgico P2/síntesis química , Antagonistas del Receptor Purinérgico P2/farmacocinética , Receptores Purinérgicos P2/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Hipertensión/tratamiento farmacológico , Piperidinas/síntesis química , Piridonas/síntesis química , Renina/antagonistas & inhibidores , Animales , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/uso terapéutico , Piridonas/química , Piridonas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Naftalenos/síntesis química , Antagonistas del Receptor Purinérgico P2/síntesis química , Receptores Purinérgicos P2 , Uridina Difosfato , Animales , Unión Competitiva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacología , Ratones , Estructura Molecular , Naftalenos/química , Naftalenos/farmacocinética , Naftalenos/farmacología , Pan troglodytes , Unión Proteica/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2/química , Antagonistas del Receptor Purinérgico P2/farmacocinética , Antagonistas del Receptor Purinérgico P2/farmacología , Receptores Purinérgicos P2Y , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Indoles/síntesis química , Indoles/farmacología , Receptores de Dopamina D2/agonistas , Amidas/química , Animales , Indoles/química , Concentración 50 Inhibidora , Ligandos , Estructura Molecular , Unión Proteica/efectos de los fármacos , RatasRESUMEN
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.
Asunto(s)
Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Dominio Catalítico , Simulación por Computador , Perros , Evaluación Preclínica de Medicamentos , Humanos , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.
Asunto(s)
Amidas/química , Indoles/química , Naftalenos/química , Quinolinas/química , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Compuestos de Sulfonilurea/química , Amidas/síntesis química , Amidas/farmacocinética , Animales , Perros , Evaluación Preclínica de Medicamentos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/farmacocinéticaRESUMEN
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.
Asunto(s)
Carbolinas/química , Enfermedades Pulmonares/tratamiento farmacológico , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Carbolinas/farmacocinética , Carbolinas/uso terapéutico , Humanos , Macaca mulatta , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relación Estructura-ActividadRESUMEN
Xenobiotics, including therapeutic agents, can produce a variety of beneficial, as well as adverse, effects in mammals. One potential source of drug-mediated toxicity stems from metabolic activation of the parent compound, typically catalyzed by one or more members of the cytochrome P450 family of enzymes. The resulting electrophile, if not quenched by low molecular weight endogenous nucleophiles, can form covalent adducts to cellular proteins, potentially resulting in enzyme inactivation, cell death, or formation of an immunogenic species. The toxicological consequences of exposure to such reactive intermediates range from mild inflammation to organ failure, anaphylaxis, and death. At Merck Research Laboratories, the potential of drug candidates to bind covalently to proteins is evaluated at the lead optimization stage of drug discovery by incubating a radiolabeled analog of the compound in question with liver microsomal preparations (under oxidative conditions) or whole cells (full cellular metabolic capability), typically derived from rat and human liver. A semi-automated method based on the Brandel Harvester technique then is used to measure the formation of covalent adducts of the test compound to liver proteins. This assay is viewed as an important component of drug discovery programs, since the findings are employed to guide specific efforts to abrogate bioactivation issues through informed structural modification of lead compounds.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Hígado/metabolismo , Proteínas/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/efectos de los fármacos , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Unión Proteica/efectos de los fármacos , Proteínas/aislamiento & purificación , Radiometría , Ratas , Conteo por Cintilación , Extracción en Fase Sólida , Soluciones , Pruebas de Toxicidad , Tritio/metabolismo , Xenobióticos/metabolismo , Xenobióticos/toxicidadRESUMEN
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
Asunto(s)
Indoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Indoles/farmacocinética , Indoles/uso terapéutico , Ligandos , Ratas , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Indoles/química , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/metabolismo , Animales , Carbolinas/química , Humanos , Indoles/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/efectos de los fármacos , Ciclopropanos/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Memoria a Largo Plazo/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Animales , Ciclopropanos/química , Ciclopropanos/uso terapéutico , Perros , Femenino , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Humanos , Macaca mulatta , Masculino , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/farmacología , Propionatos/química , Renina/antagonistas & inhibidores , Amidas/química , Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimologíaRESUMEN
The discovery of a highly potent and selective EP(4) antagonist MF-766 is discussed. This N-benzyl indole derivative exhibits good pharmacokinetic profile and unprecedented in vivo potency in the rat AIA model.
Asunto(s)
Benzoatos/farmacología , Indoles/farmacología , Dolor/tratamiento farmacológico , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Artritis/tratamiento farmacológico , Benzoatos/química , Benzoatos/uso terapéutico , Células Cultivadas , Perros , Descubrimiento de Drogas , Estabilidad de Medicamentos , Hepatocitos , Humanos , Indoles/química , Indoles/uso terapéutico , Inflamación/tratamiento farmacológico , Farmacocinética , Ratas , Subtipo EP4 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antihipertensivos/química , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Renina/antagonistas & inhibidores , Renina/metabolismo , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Humanos , Modelos Moleculares , Unión Proteica , Ratas , Ratas Sprague-Dawley , Renina/química , Relación Estructura-ActividadRESUMEN
The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.