The discovery of 2-anilinothiazolones as 11β-HSD1 inhibitors

Abstract A series of 2-anilinothiazolones were prepared as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3 , respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3 . This compound was also ∼70-fold selective over 11β-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11β-HSD1 cell assay when tested in the presence of 3% human serum albumin.