title: Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031).
abstract: ZK-807834 (also known as CI-1031) is a small molecule that potently and selectively inhibits Factor Xa. Studies in animals have shown that ZK-807834 attenuates thrombosis and thrombus progression after fibrinolysis and exhibits an increased antithrombotic-to-bleeding risk ratio compared with conventional agents. The present study describes the human in vitro anticoagulant and pharmacodynamic profile ZK-807834. Consistent with its selective inhibition of Factor Xa, ZK-807834 in the range of 0.3-0.5 microM prolonged prothrombin time (PT) and activated partial thromboplastin time (aPPT) twofold without affecting thrombin time (TT). Intersubject variability of in vitro anticoagulant activity was nominal and gender-independent. ZK-807834 inhibited Factor Xa in clot-bound prothrombinase with an average IC50 of 10+/-7 (S.D.) nM. ZK-807834 exhibited no direct effect on ADP- or collagen-induced platelet aggregation. Based on the potency and specificity, ZK-807834 may represent an important advance in the development of selective and safe antithrombotics.
authors.affiliation: Department of Pharmacology, Berlex Biosciences, 15049 San Pablo Avenue, Richmond, CA 94804, USA. joe_post@berlex.com
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Post
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Dana
authors.initials: D
authors.lastname: Abendschein
authors.forename: Janice
authors.initials: J
authors.lastname: Ewing
authors.forename: Josephine W
authors.initials: JW
authors.lastname: Hinchman
authors.forename: David R
authors.initials: DR
authors.lastname: Light
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D011517:Prothrombin Time; D011725:Pyridines / Q000494:pharmacology*; D013918:Thrombin Time; D013925:Thromboplastin / Q000037:antagonists & inhibitors
chemical_list: D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; C114592:Fidexaban; D013925:Thromboplastin