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)
Journal of Medicinal Chemistry2010Vol. 53(11), pp. 4481–4487
Citations Over TimeTop 10% of 2010 papers
Murielle M. Véniant, Clarence Hale, Randall W. Hungate, Kyung H. Gahm, Maurice G. Emery, Janan Jona, Smriti Joseph, Jeffrey A. Adams, Andrew B. Hague, George A. Moniz, Jiandong Zhang, Michael D. Bartberger, Vivian Li, Rashid Syed, Steven R. Jordan, Renée Komorowski, Michelle Chen, Rod Cupples, Ki Won Kim, David J. St. Jean, L. E. B. Johansson, Martin Henriksson, Meredith Williams, Jerk Vallgårda, Christopher Fotsch, Minghan Wang
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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