Discovery of 1-(2-Aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2‘-(aminosulfonyl)[1,1‘-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor
- 29 October 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 46 (25), 5298-5315
- https://doi.org/10.1021/jm030212h
Abstract
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.Keywords
This publication has 12 references indexed in Scilit:
- 1,2-Dibenzamidobenzene Inhibitors of Human Factor XaJournal of Medicinal Chemistry, 2000
- The Protein Data BankNucleic Acids Research, 2000
- Progress in the design of inhibitors of coagulation factor XaDrugs of the Future, 1999
- Species differences in anticoagulant and anti-Xa activity of DX-9065a, a highly selective factor Xa inhibitorThrombosis Research, 1995
- Direct thrombin inhibitors in cardiovascular medicine.Circulation, 1994
- Receptor subtypes or species homologues: relevance to drug discoveryTrends in Pharmacological Sciences, 1993
- A regioselective route to 3‐alkyl‐1‐aryl‐1H‐pyrazole‐5‐carboxylates: Synthetic studies and structural assignmentsJournal of Heterocyclic Chemistry, 1993
- Caco-2 Cell Monolayers as a Model for Drug Transport Across the Intestinal MucosaPharmaceutical Research, 1990
- Facile conversion of azides to aminesTetrahedron Letters, 1986
- Mechanism of sodium borohydride-cobaltous chloride reductionsJournal of the American Chemical Society, 1982