Title:Discovery of Chromen-7-yl Furan-2-Carboxylate as a Potent and Selective Factor XIa Inhibitor
Volume: 15
Issue: 1
Author(s): Ahmad J. Obaidullah and Rami A. Al-Horani*
Affiliation:
- 1 Drexel Drive, College of Pharmacy, Suite 327, Xavier University of Louisiana, New Orleans, LA 70125,United States
Keywords:
Factor XIa, anticoagulant, coumarin, active site inhibitor, clotting times, direct inhibition.
Abstract: Background: Direct inhibition of coagulation factor XIa (FXIa) carries a significant promise
for developing effective and safe anticoagulants.
Method: In this report, we studied 4-methyl-2-oxo-2H-chromen-7-yl furan-2-carboxylate 1, a coumarin
derivative, for direct FXIa inhibition.
Results: This small molecule was found to inhibit FXIa with an IC50 value of 0.77 µM. Coumarin 1 also
displayed a moderate-to-high selectivity for FXIa inhibition over other coagulation, digestive, and fibrinolysis
serine proteases. Coumarin 1 selectively doubled APTT of human plasma at a concentration of
72 µM. Insights about the structural features that contribute to the unique potential of such small molecule
were deduced by profiling similar molecules in PubChem Open Chemistry Database as well as by
performing a computational docking exercise.
Conclusion: Overall, chromen-7-yl furan-2-carboxylate 1 is expected to serve as an excellent fragmental
lead for further anticoagulant design and development.
