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

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 OndeykaZhiqiang Yang, Rumin Zhang, Huijun Wei, Zhicai Wu, Fengqi Zhang, Gordon Wollenberg, Tesfaye Biftu, William J. Greenlee, Madhu Chintala, Milana Maletic, Zhaoning Zhu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5575-5592
Number of pages18
JournalJournal of medicinal chemistry
Volume65
Issue number7
DOIs
StatePublished - Apr 14 2022

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

Fingerprint

Dive into the research topics of 'Lead Optimization to Advance Protease-Activated Receptor-1 Antagonists in Early Discovery'. Together they form a unique fingerprint.

Cite this