Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

作者：Taylor Steven J^*; Padyana Anil K; Abeywardane Asitha; Liang Shuang; Hao Ming Hong; De Lombaert Stephane; Proudfoot John; Farmer Bennett S III; Li Xiang; Collins Brandon; Martin Leslie; Albaugh Daniel R; Hill Drzewi Melissa; Pullen Steven S; Takahashi Hidenori

来源：Journal of Medicinal Chemistry, 2013, 56(11): 4465-4481.

DOI：10.1021/jm400138z

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.

• 出版日期2013-6-13