RESUMO
A series of benzodihydroisofurans were discovered as novel, potent, bioavailable and brain-penetrant prolylcarboxypeptidase (PrCP) inhibitors. The structure-activity relationship (SAR) is focused on improving PrCP activity and metabolic stability, and reducing plasma protein binding. In the established diet-induced obese (eDIO) mouse model, compound ent-3a displayed target engagement both in plasma and in brain. However, this compound failed to induce significant body weight loss in eDIO mice in a five-day study.
Assuntos
Carboxipeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Furanos/química , Furanos/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Estabilidade de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Furanos/síntese química , Humanos , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Efforts to modify the central proline portion of lead compound 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Especially, replacement with alanine afforded compound 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile.
Assuntos
Alanina/química , Carboxipeptidases/antagonistas & inibidores , Descoberta de Drogas , Alanina/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity (32a, IC(50)=43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).
Assuntos
Aminas/síntese química , Encéfalo/efeitos dos fármacos , Carboxipeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Amidas/química , Aminas/química , Aminas/farmacologia , Animais , Encéfalo/enzimologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/química , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
RESUMO
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.