2-(S)-phenethylaminothiazolones as potent, orally efficacious inhibitors of 11β-hydroxysteriod dehydrogenase type 1

11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11 beta-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a K-i of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11 beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.