RESUMEN
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.
Asunto(s)
Carboxipeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Furanos/química , Furanos/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Activación Enzimática/efectos de los fármacos , Furanos/síntesis química , Humanos , Ratones , Ratones Obesos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Aminas/síntesis química , Encéfalo/efectos de los fármacos , Carboxipeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Amidas/química , Aminas/química , Aminas/farmacología , Animales , Encéfalo/enzimología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/química , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Alanina/química , Carboxipeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Alanina/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of benzimidazole pyrrolidinyl amides containing a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC(50)'s were achieved for several analogs, of which compound 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compound 9b was also studied in vivo for its effect on weight loss and food intake in an eDIO mouse model and the results will be discussed.