2. Academic Validation
  3. Discovery of potent, selective chymase inhibitors via fragment linking strategies

Discovery of potent, selective chymase inhibitors via fragment linking strategies

  • J Med Chem. 2013 Jun 13;56(11):4465-81. doi: 10.1021/jm400138z.
Steven J Taylor 1,  Anil K Padyana,  Asitha Abeywardane,  Shuang Liang,  Ming-Hong Hao,  Stéphane De Lombaert,  John Proudfoot,  Bennett S Farmer 3rd,  Xiang Li,  Brandon Collins,  Leslie Martin,  Daniel R Albaugh,  Melissa Hill-Drzewi,  Steven S Pullen,  Hidenori Takahashi
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. [email protected]
PMID: 23659209 DOI: 10.1021/jm400138z
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.

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