Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring

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 C log P and improved off-target selectivity compared to an earlier development candidate.

The SAR of the pyridine ring of himbacine derived thrombin receptor (PAR-1) antagonists is described.Figure optionsDownload as PowerPoint slide