Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies
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- 作者：Steven J. Taylor ; Anil K. Padyana ; Asitha Abeywardane ; Shuang Liang ; Ming-Hong Hao ; St茅phane De Lombaert ; John Proudfoot ; Bennett S. Farmer ; III ; Xiang Li ; Brandon Collins ; Leslie Martin ; Daniel R. Albaugh ; Melissa Hill-Drzewi ; Steven S. Pullen ; Hidenori Takahashi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：June 13, 2013
- 年：2013
- 卷：56
- 期：11
- 页码：4465-4481
- 全文大小：844K
- 年卷期：v.56,no.11(June 13, 2013)
- ISSN：1520-4804
文摘
Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.