Document Detail

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).
MedLine Citation:
PMID:  20465278     Owner:  NLM     Status:  MEDLINE    
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.
Murielle M V?niant; 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; Ren?e Komorowski; Michelle M Chen; Rod Cupples; Ki Won Kim; David J St Jean; Lars Johansson; Martin A Henriksson; Meredith Williams; Jerk Vallg?rda; Christopher Fotsch; Minghan Wang
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-03     Completed Date:  2010-07-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4481-7     Citation Subset:  IM    
Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
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MeSH Terms
11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*,  chemistry
Administration, Oral
Drug Discovery / methods*
Enzyme Inhibitors / administration & dosage*,  chemistry,  pharmacokinetics,  pharmacology*
Models, Molecular
Protein Conformation
Thiazoles / administration & dosage*,  chemistry,  pharmacokinetics,  pharmacology*
Reg. No./Substance:
0/AMG 221; 0/Enzyme Inhibitors; 0/Thiazoles; EC Dehydrogenase Type 1

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