Abstract
Discoveries that lead to ZK 807834 (CI-1031, 2a), a potent and selective factor Xa (fXa) inhibitor currently in clinical testing as an intravenous antithrombotic, were initiated by the identification of the potent (Z,Z)-isomer of BABCH (1c). A structure-activity relationship (SAR) was established with a series of analogues of BABCH. This SAR database, combined with compu-ter modeling, demonstrated that binding of the second basic group in the S3 S4 pocket provided fXa potency and that a carboxylic acid group on the opposite side of the molecule resulted in selectivity versus thrombin. Simple substitution of a cyclic urea for the unsaturated ketone structure of BABCH gave disappointing results, but discovery of the bisphenoxy-pyridine analogues provided a template that could be readily optimized. The SAR established for this template is described and compared with computer modeling, REDOR NMR and X-ray crystallography studies. Inhibitor binding to fXa was increased by the introduction of a hydroxyl group on the proximal phenylamidine ring and by the introduction of fluorine atoms at C-3 and C-5 of the pyridine ring. Pharmacokinetic parameters were improved by balancing the contributions from the substituents on the distal ring and the central pyridine ring. The optimal combination was a methyl-(2H)-imidazoline group on the distal ring and a sarcosine at C-4 of the pyridine ring. The promising preclinical database for CI-1031 is described. This review relates the SAR leading to the discovery of the clinical candidate, CI-1031 directly to our best understanding of how this potent inhibitor interacts with the fXa active site.
Keywords: Factor Xa Inhibitor, CYCLIC KETONE fXa INHIBITORS, UREA fXa INHIBITORS, DIPHENOXYPYRIDINE, BOVINE TRYPSIN, MONOAMIDINE INHIBITORS
Current Topics in Medicinal Chemistry
Title: Discovery of the Factor Xa Inhibitor, ZK 807834 (CI-1031)
Volume: 1 Issue: 2
Author(s): David R. Light and William J. Guilford
Affiliation:
Keywords: Factor Xa Inhibitor, CYCLIC KETONE fXa INHIBITORS, UREA fXa INHIBITORS, DIPHENOXYPYRIDINE, BOVINE TRYPSIN, MONOAMIDINE INHIBITORS
Abstract: Discoveries that lead to ZK 807834 (CI-1031, 2a), a potent and selective factor Xa (fXa) inhibitor currently in clinical testing as an intravenous antithrombotic, were initiated by the identification of the potent (Z,Z)-isomer of BABCH (1c). A structure-activity relationship (SAR) was established with a series of analogues of BABCH. This SAR database, combined with compu-ter modeling, demonstrated that binding of the second basic group in the S3 S4 pocket provided fXa potency and that a carboxylic acid group on the opposite side of the molecule resulted in selectivity versus thrombin. Simple substitution of a cyclic urea for the unsaturated ketone structure of BABCH gave disappointing results, but discovery of the bisphenoxy-pyridine analogues provided a template that could be readily optimized. The SAR established for this template is described and compared with computer modeling, REDOR NMR and X-ray crystallography studies. Inhibitor binding to fXa was increased by the introduction of a hydroxyl group on the proximal phenylamidine ring and by the introduction of fluorine atoms at C-3 and C-5 of the pyridine ring. Pharmacokinetic parameters were improved by balancing the contributions from the substituents on the distal ring and the central pyridine ring. The optimal combination was a methyl-(2H)-imidazoline group on the distal ring and a sarcosine at C-4 of the pyridine ring. The promising preclinical database for CI-1031 is described. This review relates the SAR leading to the discovery of the clinical candidate, CI-1031 directly to our best understanding of how this potent inhibitor interacts with the fXa active site.
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Cite this article as:
Light R. David and Guilford J. William, Discovery of the Factor Xa Inhibitor, ZK 807834 (CI-1031), Current Topics in Medicinal Chemistry 2001; 1 (2) . https://dx.doi.org/10.2174/1568026013395498
DOI https://dx.doi.org/10.2174/1568026013395498 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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