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

  • J Med Chem. 2007 Feb 8;50(3):429-32. doi: 10.1021/jm061214f.
David J St Jean Jr  1 ,  Chester Yuan ,  Eric A Bercot ,  Rod Cupples ,  Michelle Chen ,  Jenne Fretland ,  Clarence Hale ,  Randall W Hungate ,  Renee Komorowski ,  Murielle Veniant ,  Minghan Wang ,  Xiping Zhang ,  Christopher Fotsch
Affiliations
  • 1. Department of Medicinal Chemistry, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. [email protected]
PMID: 17266194 DOI: 10.1021/jm061214f
Abstract

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-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 Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.