RESUMO
Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50â¯=â¯4â¯nM) with no CYP inhibitory activity (IC50 >10⯵M). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.
Assuntos
Cicloexanos/farmacologia , Desenho de Fármacos , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Espiro/farmacologia , Animais , Cicloexanos/síntese química , Cicloexanos/química , Relação Dose-Resposta a Droga , Glucose/administração & dosagem , Glucose/análise , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Injeções Intraperitoneais , Insulina/metabolismo , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp),1,2 we extended the structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group and succeeded in a significant advancement of activity. Starting from compound 1, optimization of the A, B, and C rings afforded potent inhibitors with low nanomolar potency against genotype 1b NS5B. The compounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficiently blocked subgenomic viral RNA replication in the replicon cell assay at low submicromolar concentrations. Among the new compounds, compound 10n (JTK-109) exhibited favorable pharmacokinetic profiles, high selectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatment of hepatitis C.
Assuntos
Antivirais/síntese química , Benzimidazóis/síntese química , Compostos de Bifenilo/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Hepacivirus/genética , Humanos , Fígado/metabolismo , Ratos , Replicon , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
Monoacylglycerol acyltransferase 2 (MGAT2) plays an important role in intestinal fat absorption. We discovered the novel MGAT2 inhibitor, JTP-103237, and evaluated its pharmacological profile. JTP-103237 selectively inhibited MGAT2 without remarkable species differences and reduced absorbed lipids in circulation. After lipid administration, JTP-103237 slightly but significantly decreased triglyceride content in proximal small intestine and significantly increased the lipids content in the distal small intestine. In addition, JTP-103237 significantly increased MGAT substrate (monoacylglycerol and fatty acid) content in the small intestine. JTP-103237 increased plasma peptide YY levels after lipid loading and reduced food intake in a dietary fat-dependent manner. After chronic treatment, JTP-103237 significantly decreased body weight and increased O2 consumption in the early dark phase in high fat diet induced obese (DIO) mice. Moreover, JTP-103237 improved glucose tolerance and decreased fat weight and hepatic triglyceride content in DIO mice. Our findings indicate that JTP-103237 prevents diet-induced obesity by inhibiting intestinal MGAT2 and has unique properties as a drug for the treatment of obesity.