Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis.
J Med Chem, 2024/3/14;67(5):3571-3589.
Zhang X[1], Jiang W[1], Richter JM[1], Bates JA[1], Reznik SK[1], Stachura S[1], Rampulla R[1], Doddalingappa D[2], Ulaganathan S[2], Hua J[1], Bostwick JS[1], Sum C[1], Posy S[1], Malmstrom S[1], Dickey J[1], Harden D[1], Lawrence RM[1], Guarino VR[1], Schumacher WA[1], Wong P[1], Yang J[1], Gordon DA[1], Wexler RR[1], Priestley ES[1]
Affiliations
PMID: 38385264DOI: 10.1021/acs.jmedchem.3c01986
Impact factor: 8.039
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.
MeSH terms
Animals; Fibrinolytic Agents; Macaca fascicularis; Quinoxalines; Receptors, Thrombin; Thrombin; Hemorrhage; Thrombosis; Receptor, PAR-1; Blood Platelets; Platelet Aggregation
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