Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.
Research article published in Journal of medicinal chemistry (2001)
Abstract
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex,...
Por qué esto importa para la hirudoterapia
This study reports the discovery and optimization of DPC423, a highly potent, selective, and orally bioavailable pyrazole-based inhibitor of blood coagulation factor Xa, developed through modification of an earlier isoxazoline/isoxazole inhibitor series that showed good potency in animal thrombosis models. The researchers improved oral bioavailability by replacing a highly basic benzamidine group with a less basic benzylamine moiety, ultimately selecting DPC423 for clinical development. The abstract makes no mention of leeches, hirudin, hirudotherapy, or leech-derived molecules. The article's connection to the American Society of Hirudotherapy is therefore nonexistent based on the abstract; it concerns synthetic small-molecule anticoagulant drug design targeting factor Xa rather than any leech-related topic.
Citación
Discovery of 1-[3-(aminomethyl)phenyl]-N-3-fluoro-2'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.
Pinto et al. · Journal of medicinal chemistry, 2001
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Añadido a la biblioteca ASH: May 28, 2026 · Última actualización del sitio: June 18, 2026