ACS Medicinal Chemistry Letters p. 561 - 565 (2014)
Update date:2022-08-05
Topics:
Chelliah, Mariappan V.
Eagen, Keith
Guo, Zhuyan
Chackalamannil, Samuel
Xia, Yan
Tsai, Hsingan
Greenlee, William J.
Ahn, Ho-Sam
Kurowski, Stan
Boykow, George
Hsieh, Yunsheng
Chintala, Madhu
We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series.
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