Discovery of a Potent, Orally Active 11β-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)

Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11β-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 epi...

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Published in:Journal of medicinal chemistry 2010-06, Vol.53 (11), p.4481-4487
Main Authors: Véniant, Murielle M, Hale, Clarence, Hungate, Randall W, Gahm, Kyung, Emery, Maurice G, Jona, Janan, Joseph, Smriti, Adams, Jeffrey, Hague, Andrew, Moniz, George, Zhang, Jiandong, Bartberger, Michael D, Li, Vivian, Syed, Rashid, Jordan, Steven, Komorowski, Renée, Chen, Michelle M, Cupples, Rod, Kim, Ki Won, St. Jean, David J, Johansson, Lars, Henriksson, Martin A, Williams, Meredith, Vallgårda, Jerk, Fotsch, Christopher, Wang, Minghan
Format: Article
Language:English
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Summary:Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11β-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100242d