Further studies with the 2-amino-1,3-thiazol-4(5H)-one class of 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: reducing pregnane X receptor activity and exploring activity in a monkey pharmacodynamic model

J Med Chem. 2008 Dec 25;51(24):7953-67. doi: 10.1021/jm801073z.

Christopher Fotsch ¹, Michael D Bartberger, Eric A Bercot, Michelle Chen, Rod Cupples, Maury Emery, Jenne Fretland, Anil Guram, Clarence Hale, Nianhe Han, Dean Hickman, Randall W Hungate, Michael Hayashi, Renee Komorowski, Qingyian Liu, Guy Matsumoto, David J St Jean Jr, Stefania Ursu, Murielle Véniant, Guifen Xu, Qiuping Ye, Chester Yuan, Jiandong Zhang, Xiping Zhang, Hua Tu, Minghan Wang

Affiliations

Affiliation

1 Department of Chemical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. cfotsch@amgen.com

PMID: 19053753 DOI: 10.1021/jm801073z

Abstract

A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the Enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.

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