Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221)

  • J Med Chem. 2010 Jun 10;53(11):4481-7. doi: 10.1021/jm100242d.
Murielle M Véniant  1 ,  Clarence Hale ,  Randall W Hungate ,  Kyung Gahm ,  Maurice G Emery ,  Janan Jona ,  Smriti Joseph ,  Jeffrey Adams ,  Andrew Hague ,  George Moniz ,  Jiandong Zhang ,  Michael D Bartberger ,  Vivian Li ,  Rashid Syed ,  Steven Jordan ,  Renée Komorowski ,  Michelle M Chen ,  Rod Cupples ,  Ki Won Kim ,  David J St Jean Jr ,  Lars Johansson ,  Martin A Henriksson ,  Meredith Williams ,  Jerk Vallgårda ,  Christopher Fotsch ,  Minghan Wang
Affiliations
  • 1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
PMID: 20465278 DOI: 10.1021/jm100242d
Abstract

Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and Insulin levels and reduced body weight in diet-induced Obesity mice.

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