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Discovery of potent, selective chymase inhibitors via fragment linking strategies.
|Title||Discovery of potent, selective chymase inhibitors via fragment linking strategies.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Taylor SJ, Padyana AK, Abeywardane A, Liang S, Hao M-H, De Lombaert S, Proudfoot J, Farmer BS, Li X, Collins B, Martin L, Albaugh DR, Hill-Drzewi M, Pullen SS, Takahashi H|
|Journal||Journal of medicinal chemistry|
|Date Published||2013 Jun 13|
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.
|Alternate Journal||J. Med. Chem.|