Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

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...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 56; no. 11; pp. 4465 - 4481
Main Authors Taylor, Steven J, Padyana, Anil K, Abeywardane, Asitha, Liang, Shuang, Hao, Ming-Hong, De Lombaert, Stéphane, Proudfoot, John, Farmer, Bennett S, Li, Xiang, Collins, Brandon, Martin, Leslie, Albaugh, Daniel R, Hill-Drzewi, Melissa, Pullen, Steven S, Takahashi, Hidenori
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.06.2013
Amer Chemical Soc
Subjects
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - metabolism
Cardiovascular Agents - chemical synthesis
Cardiovascular Agents - chemistry
Cardiovascular Agents - metabolism
Catalytic Domain
Chemistry, Medicinal
Chymases - antagonists & inhibitors
Chymases - chemistry
Crystallography, X-Ray
Humans
In Vitro Techniques
Life Sciences & Biomedicine
Microsomes, Liver - metabolism
Models, Molecular
Molecular Structure
Pharmacology & Pharmacy
Protein Binding
Science & Technology
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - metabolism
Structure-Activity Relationship
FIBROSIS
TARGET
INFARCTION
MECHANISMS
PATHOPHYSIOLOGICAL ROLE
MAST-CELLS
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Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0022-2623
1520-4804
DOI:10.1021/jm400138z