Q4 · MEDICINE
Article
Author: Sun, Shaoyi ; Pokrovskaia, Natalia ; Fu, Jianmin ; Tran, Jennifer ; Dales, Natalie A ; Chowdhury, Sultan ; Ratkay, Leslie G ; Jia, Qi ; Fonarev, Julia ; Radomski, Chris ; McLaren, David G ; Winther, Michael D ; Zhang, Zaihui ; Kodumuru, Vishnumurthy ; Leung, Po-Yee ; Hubbard, Brian
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.