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).

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.

• Authors: Murielle M Véniant, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 11 Pg. 4481-7 (Jun 10 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20465278 (Publication Type: Journal Article)

Chemical References

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

Topics

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