Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis.
J Med Chem
; 67(5): 3571-3589, 2024 Mar 14.
Article
in En
| MEDLINE
| ID: mdl-38385264
ABSTRACT
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low µM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thrombosis
/
Fibrinolytic Agents
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: