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
  • 1. Department of Chemical Research and Development, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. [email protected]
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.