RESUMO
PURPOSE: The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations. METHOD: For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. RESULT: The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.
Assuntos
Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Tecnologia Farmacêutica/métodos , Animais , Células CACO-2 , Estabilidade Enzimática/efeitos dos fármacos , Estabilidade Enzimática/fisiologia , Previsões , Humanos , Macaca fascicularis , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Microssomos Hepáticos/efeitos dos fármacosRESUMO
In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.
Assuntos
Autorreceptores/antagonistas & inibidores , Fármacos do Sistema Nervoso Central/síntese química , Antagonistas Muscarínicos/síntese química , Piperidinas/síntese química , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/metabolismo , Administração Oral , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Humanos , Técnicas In Vitro , Microdiálise , Conformação Molecular , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.