title: Discovery of potent, selective chymase inhibitors via fragment linking strategies.
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.
authors: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. steven.taylor@boehringeringelheim.com
authors: Steven J
authors: SJ
authors: Taylor
authors: Anil K
authors: AK
authors: Padyana
authors: Asitha
authors: A
authors: Abeywardane
authors: Shuang
authors: S
authors: Liang
authors: Ming-Hong
authors: MH
authors: Hao
authors: Stéphane
authors: S
authors: De Lombaert
authors: John
authors: J
authors: Proudfoot
authors: Bennett S
authors: BS
authors: Farmer
authors: Xiang
authors: X
authors: Li
authors: Brandon
authors: B
authors: Collins
authors: Leslie
authors: L
authors: Martin
authors: Daniel R
authors: DR
authors: Albaugh
authors: Melissa
authors: M
authors: Hill-Drzewi
authors: Steven S
authors: SS
authors: Pullen
authors: Hidenori
authors: H
authors: Takahashi
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D002317:Cardiovascular Agents; D015842:Serine Proteinase Inhibitors; D053818:Chymases