The development and SAR of pyrrolidine carboxamide 11β-HSD1 inhibitors
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- 作者：Hengmiao Cheng ; Jacqui Hoffman ; Phuong Le ; Sajiv K. Nair ; Stephan Cripps ; Jean Matthews ; Christopher Smith ; Michele Yang ; Stan Kupchinsky ; Klaus Dress ; Martin Edwards ; Bridget Cole ; Evan Walters ; Chri
- 关键词：11β ; -HSD1 ; Inhibitor ; Diabetes ; Pyrrolidine carboxamide ; PF-877423
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2010
- 出版时间：1 May 2010
- 年：2010
- 卷：20
- 期：9
- 页码：2897-2902
- 全文大小：611 K
文摘
The design and development of a series of highly selective pyrrolidine carboxamide 11β-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11β-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11β-HSD1 selective inhibitor 42.