RESUMO
A series of structurally novel stearoyl-CoA desaturase-1 (SCD-1) inhibitors has been identified by optimizing a hit from our corporate library. Preliminary structure-activity relationship (SAR) studies led to the discovery of the highly potent and orally bioavailable thiazole-based SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a).
Assuntos
Benzamidas/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Estearoil-CoA Dessaturase/antagonistas & inibidores , Tiazóis/síntese química , Administração Oral , Animais , Área Sob a Curva , Benzamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Químicos , Estearoil-CoA Dessaturase/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
