title: Design, synthesis, and biological activity of potent and selective inhibitors of blood coagulation factor Xa.
abstract: Factor Xa (FXa) has materialized as a key enzyme for the intervention of the blood coagulation cascade and for the development of new antithrombotic agents. FXa is the lone enzyme responsible for the production of thrombin and therefore is an attractive target for the control of thrombus formation. We have designed and synthesized a unique series of quinoxalinone FXa inhibitors. This series resulted in 3-[4-[5-((2S,6R)-2,6-dimethylpiperidin-1-yl)pentyl]-3-oxo-3,4-dihydroquinoxolin-2-yl]benzamidine (35) with 0.83 nM activity against FXa and excellent selectivity over similar serine proteases. An X-ray crystal structure of compound 35 bound to trypsin along with molecular modeling has led to a predicted binding conformation of compound 35 in FXa. Compound 35 has also been proven to be efficacious in vivo in both the rabbit veno-venous shunt and dog electrolytic injury models. In addition, it was shown that compound 35 did not significantly increase bleeding times in a rabbit model except at the highest doses and plasma concentrations were elevated in a dose dependent manner following a bolus dose and continuous intravenous infusion.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Liguo
authors.initials: L
authors.lastname: Chi
authors.forename: Thomas B
authors.initials: TB
authors.lastname: McClanahan
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mertz
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Potoczak
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Narasimhan
authors.forename: Debra R
authors.initials: DR
authors.lastname: Holland
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Rapundalo
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013045:Species Specificity; D013927:Thrombosis / Q000473:pathology / Q000517:prevention & control
chemical_list: C488672:3-(4-(5-(2,6-dimethylpiperidin-1-yl)pentyl)-3-oxo-3,4-dihydroxyquinoxalin-2-yl)benzamidine; D000925:Anticoagulants; D001550:Benzamidines; D065427:Factor Xa Inhibitors; D011810:Quinoxalines; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa