PMID: 11899248Mar 20, 2002Paper

Discovery of the factor Xa inhibitor, ZK 807834 (CI-1031)

Current Topics in Medicinal Chemistry
D R Light, William J Guilford

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 computer 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 an...Continue Reading

Citations

Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jean M J Fréchet
Aug 5, 2009·The Journal of Clinical Investigation·Chris J ScottonRachel C Chambers
May 2, 2003·Expert Opinion on Investigational Drugs·Johannes Ruef, Hugo A Katus
Jan 27, 2004·The Annals of Pharmacotherapy·Edith A Nutescu, Ann K Wittkowsky
May 28, 2010·Journal of Medicinal Chemistry·Donald J P PintoRuth R Wexler
May 31, 2002·Journal of Medicinal Chemistry·Gary PhillipsMichael M Morrissey

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