AI Article Synopsis
- - PAR4 is a potential target for developing new antithrombotic drugs that could reduce bleeding risks compared to current treatments.
- - Researchers discovered a promising compound through high-throughput screening (HTS) and improved it using structural optimizations, resulting in a new series that effectively blocks PAR4.
- - The leading compound showed exceptional potency (2 nM IC) against PAR4 and significant selectivity, making it highly effective in preventing thrombosis with minimal bleeding side effects in monkey models.
Article 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 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 , possessing a 2 nM IC 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c01986 | DOI Listing |
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