Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery

  • J Med Chem. 2022 Apr 14;65(7):5575-5592. doi: 10.1021/acs.jmedchem.1c02048.
Mihirbaran Mandal ,  Maria Madeira ,  Rupesh P Amin ,  Alexei V Buevich ,  Alan Cheng ,  Marc Labroli ,  Xiaoxiang Liu ,  John Acton ,  Barbara Pio ,  Andrea Basso ,  Harry Chobanian ,  Grace Dong ,  Jamie Dropinski ,  Yan Guo ,  Zhuyan Guo ,  Stan Kurowski ,  Walter Korfmacher ,  Sandra Lee ,  Dongfang Meng ,  Debra Ondeyka ,  Zhiqiang Yang ,  Rumin Zhang ,  Huijun Wei ,  Zhicai Wu ,  Fengqi Zhang ,  Gordon Wollenberg ,  Tesfaye Biftu ,  William J Greenlee ,  Madhu Chintala ,  Milana Maletic ,  Zhaoning Zhu
PMID: 35349275 DOI: 10.1021/acs.jmedchem.1c02048
Abstract

Vorapaxar is an approved drug for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Subsequent to the discovery of Vorapaxar, medicinal chemistry efforts were continued to identify structurally differentiated leads. Toward this goal, extensive structure-activity relationship studies using a C-ring-truncated version of Vorapaxar culminated in the discovery of three leads, represented as 13, 14, and 23. Among these leads, compound 14 possessed favorable pharmacokinetic properties and an off-target profile, which supported additional profiling in an exploratory rat toxicology study.

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