2. Academic Validation
  3. 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)

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

Affiliation

  • 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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