Further Studies with the 2-Amino-1,3-thiazol-4(5H)-one Class of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors: Reducing Pregnane X Receptor Activity and Exploring Activity in a Monkey
详细信息 查看全文
- 作者：Christopher Fotsch ; 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 Hay
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：December 25, 2008
- 年：2008
- 卷：51
- 期：24
- 页码：7953-7967
- 全文大小：325K
- 年卷期：v.51,no.24(December 25, 2008)
- ISSN：1520-4804
文摘
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11β-HSD1 activity after being orally administered.