2. Academic Validation
  3. Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery

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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