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Published on: May 24, 2024
Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring
Yan Xia1, Samuel Chackalamannil, Martin Clasby
1Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@spcorp.com
Abstract:
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
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