Abstract
Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culminated in the discovery of DPC 423. DPC 423 was selected for clinical evaluation as a potent and orally bioavailable fXa inhibitor.
Keywords: Factor Xa Inhibitors, Thrombosis, DIBASIC FXA INHIBITORS, N,N-disubstituted Anilines, Pyrrolidines and Isoxazolidines, BENZYLAMINE FXA INHIBITORS, Pyrazoles
Current Topics in Medicinal Chemistry
Title: The Design and Synthesis of Noncovalent Factor Xa Inhibitors
Volume: 1 Issue: 2
Author(s): M. L. Quan and R. R. Wexler
Affiliation:
Keywords: Factor Xa Inhibitors, Thrombosis, DIBASIC FXA INHIBITORS, N,N-disubstituted Anilines, Pyrrolidines and Isoxazolidines, BENZYLAMINE FXA INHIBITORS, Pyrazoles
Abstract: Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culminated in the discovery of DPC 423. DPC 423 was selected for clinical evaluation as a potent and orally bioavailable fXa inhibitor.
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Cite this article as:
Quan L. M. and Wexler R. R., The Design and Synthesis of Noncovalent Factor Xa Inhibitors, Current Topics in Medicinal Chemistry 2001; 1 (2) . https://dx.doi.org/10.2174/1568026013395407
DOI https://dx.doi.org/10.2174/1568026013395407 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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