RESUMEN

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.

Asunto(s)

Amidas/química , Descubrimiento de Drogas/métodos , Imidazolidinas/química , Enfermedades Metabólicas , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Amidas/farmacología , Amidas/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Células Hep G2 , Humanos , Imidazolidinas/farmacología , Imidazolidinas/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/enzimología , Ratones , Ratas , Ratas Sprague-Dawley , Estearoil-CoA Desaturasa/metabolismo