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.

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.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
  • Administration, Oral
  • Animals
  • Dogs
  • Drug Discovery / methods*
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Rats
  • Thiazoles / administration & dosage*
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*

Substances

  • AMG 221
  • Enzyme Inhibitors
  • Thiazoles
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1