1. Academic Validation
  2. Coumarins as factor XIIa inhibitors: Potency and selectivity improvements using a fragment-based strategy

Coumarins as factor XIIa inhibitors: Potency and selectivity improvements using a fragment-based strategy

  • Eur J Med Chem. 2023 Nov 5;259:115636. doi: 10.1016/j.ejmech.2023.115636.
Clara Davoine 1 Amandine Traina 2 Jonathan Evrard 2 Steve Lanners 2 Marianne Fillet 3 Lionel Pochet 4
Affiliations

Affiliations

  • 1 Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium; Laboratory for the Analysis of Medicines (LAM), Department of Pharmacy, CIRM, University of Liege, Place Du 20 Août 7, 4000, Liège, Belgium.
  • 2 Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium.
  • 3 Laboratory for the Analysis of Medicines (LAM), Department of Pharmacy, CIRM, University of Liege, Place Du 20 Août 7, 4000, Liège, Belgium.
  • 4 Namur Medicine & Drug Innovation Center (NAMEDIC - NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium. Electronic address: lionel.pochet@unamur.be.
Abstract

Previously, we described weak coumarin inhibitors of factor XIIa, a promising target for artificial surface-induced thrombosis and various inflammatory diseases. In this work, we used fragment-based drug discovery approach to improve our coumarin series. First, we screened about 200 fragments for the S1 pocket. The S1 pocket of trypsin-like serine proteases, such as factor XIIa, is highly conserved and is known to drive a major part of the association energy. From the screening, we selected fragments displaying a micromolar activity and studied their selectivity on other serine proteases. Then, these fragments were merged to our coumarin templates, leading to the generation of nanomolar inhibitors. The mechanism of inhibition was further studied by mass spectrometry demonstrating the covalent binding through the formation of an acyl Enzyme complex. The most potent compound was tested in plasma to evaluate its stability and efficacy on coagulation assays. It exhibited a plasmatic half-life of 1.9 h and a good selectivity for the intrinsic coagulation pathway over the extrinsic one.

Keywords

Biochemical assay; Coumarin; Factor XIIa; Fragment-based drug discovery; Medical device-induced thrombosis; Serine proteinase inhibitors.

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