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J Med Chem. 2013 Jun 13;56(11):4465-81. doi: 10.1021/jm400138z. Epub 2013 Jun 4.

Discovery of potent, selective chymase inhibitors via fragment linking strategies.

Author information

1
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. steven.taylor@boehringeringelheim.com

Abstract

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.

PMID:
23659209
DOI:
10.1021/jm400138z
[Indexed for MEDLINE]

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