Author/Authors :
Yan Xia، نويسنده , , Samuel Chackalamannil، نويسنده , , Martin Clasby، نويسنده , , Dario Doller، نويسنده , , Keith Eagen، نويسنده , , William J. Greenlee، نويسنده , , Hsingan Tsai، نويسنده , , Jacqueline Agans-Fantuzzi، نويسنده , , Ho-Sam Ahn، نويسنده , , George C. Boykow، نويسنده , , Yunsheng Hsieh، نويسنده , , Charles A. Lunn، نويسنده , , Madhu Chintala، نويسنده ,
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 C log P and improved off-target selectivity compared to an earlier development candidate.
Keywords :
PAR-1 Antagonist , Structure–activity relationship , SAR , pyridine , Himbacine , Thrombin receptor antagonist
