title: Discovery of the factor Xa inhibitor, ZK 807834 (CI-1031).
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 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.
authors.affiliation: Cardiovascular Research, Berlex Biosciences, Richmond, CA 94804-0099, USA. david_light@berlex.com
authors.forename: D R
authors.initials: DR
authors.lastname: Light
authors.forename: W J
authors.initials: WJ
authors.lastname: Guilford
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D000578:Amidines; D000925:Anticoagulants; D001597:Benzylidene Compounds; D065427:Factor Xa Inhibitors; D011725:Pyridines; D014361:Trypsin Inhibitors; C114591:ZK 805412; C114592:Fidexaban