RESUMO
A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.
Assuntos
Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ureia/químicaRESUMO
Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
Assuntos
Oxidiazóis/síntese química , Piridazinas/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Acil Coenzima A/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of novel stearoyl-CoA desaturase 1 (SCD1) inhibitors were identified by scaffold design based on known SCD1 inhibitors. Large structural changes were made leading to multiple analogs with comparable or improved potency. This approach is valuable for generation of proprietary compounds without conducting a costly high-throughput screening.