RESUMO
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
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
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
Novel prolylcarboxypeptidase (PrCP) inhibitors with nanomolar IC(50) values were prepared by replacing the previously described dichlorobenzimidazole-substituted pyrrolidine amides with a variety of substituted benzylamine amides. In contrast to prior series, the compounds demonstrated minimal inhibition shift in whole serum and minimal recognition by P-glycoprotein (P-gp) efflux transporters. The compounds were also cell permeable and demonstrated in vivo brain exposure. The in vivo effect of compound (S)-6e on weight loss in an established diet-induced obesity (eDIO) mouse model was studied.
Assuntos
Benzimidazóis/farmacologia , Encéfalo/metabolismo , Carboxipeptidases/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Amidas/química , Animais , Transporte Biológico , Peso Corporal , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Obesidade/tratamento farmacológico , Pirrolidinas/química , Fatores de TempoRESUMO
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.
Assuntos
Amidas , Benzimidazóis , Carboxipeptidases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos , Pirrolidinas , Amidas/química , Amidas/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
Assuntos
Fármacos Antiobesidade/síntese química , Benzimidazóis/síntese química , Carboxipeptidases/antagonistas & inibidores , Fenilalanina/análogos & derivados , Inibidores de Serina Proteinase/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Carboxipeptidases/genética , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Ligação Proteica , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.