2. Academic Validation
  3. Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors

Discovery of novel N-acylpyrazoles as potent and selective thrombin inhibitors

  • Eur J Med Chem. 2022 Oct 27;246:114855. doi: 10.1016/j.ejmech.2022.114855.
Kevin M Short 1,  M Angels Estiarte 2,  Son M Pham 2,  David C Williams 2,  Lev Igoudin 2,  Subhadra Dash 2,  Nichole Sandoval 2,  Anirban Datta 2,  Nicola Pozzi 3,  Enrico Di Cera 3,  David B Kita 2
Affiliations

Affiliations

  • 1 Verseon, 47071 Bayside Parkway, Fremont, CA, 94538, USA. Electronic address: kshort@verseon.com.
  • 2 Verseon, 47071 Bayside Parkway, Fremont, CA, 94538, USA.
  • 3 Department of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, 1100 South Grand Blvd., St. Louis, MO, 63104, USA.
PMID: 36462436 DOI: 10.1016/j.ejmech.2022.114855
Abstract

Direct oral anticoagulants (DOACs), which includes Thrombin and Factor Xa inhibitors, have emerged as the preferred therapeutics for thrombotic disorders, penetrating a market previously dominated by warfarin and heparin. This article describes the discovery and profiling of a novel series of N-acylpyrazoles, which act as selective, covalent, reversible, non-competitive inhibitors of Thrombin. We describe in vitro stability issues associated with this chemotype and, importantly, demonstrate that N-acylpyrazoles successfully act in vivo as anticoagulants in basic thrombotic animal models. Crucially, this anticoagulant nature is unaccompanied by the higher bleeding risk profile that has become an undesirable characteristic of the DTIs and Factor Xa inhibitors. We propose that the N-acylpyrazole chemotype shows intriguing promise as next-generation oral anticoagulants.

Keywords

Anticoagulants; Covalent; N-Acylpyrazoles; Thrombin.

Figures
Products