title: Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors.
abstract: There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
authors.affiliation: Berlex Biosciences, Post Office Box 4099, Richmond, California 94804-0099, USA. rickbinye@yahoo.com
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Damian O
authors.initials: DO
authors.lastname: Arnaiz
authors.forename: Yuo-Ling
authors.initials: YL
authors.lastname: Chou
authors.forename: Brian D
authors.initials: BD
authors.lastname: Griedel
authors.forename: Rushad
authors.initials: R
authors.lastname: Karanjawala
authors.forename: Wheeseong
authors.initials: W
authors.lastname: Lee
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: Karna L
authors.initials: KL
authors.lastname: Sacchi
authors.forename: Steven T
authors.initials: ST
authors.lastname: Sakata
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: Shung C
authors.initials: SC
authors.lastname: Wu
authors.forename: Zuchun
authors.initials: Z
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Sarah
authors.initials: S
authors.lastname: Cheeseman
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
authors.forename: Janice
authors.initials: J
authors.lastname: Ewing
authors.forename: Richard
authors.initials: R
authors.lastname: Fitch
authors.forename: Dao
authors.initials: D
authors.lastname: Lentz
authors.forename: Amy
authors.initials: A
authors.lastname: Liang
authors.forename: David
authors.initials: D
authors.lastname: Light
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Joseph
authors.initials: J
authors.lastname: Post
authors.forename: Galina
authors.initials: G
authors.lastname: Rumennik
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Ron
authors.initials: R
authors.lastname: Vergona
authors.forename: Janette
authors.initials: J
authors.lastname: Walters
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Kathy A
authors.initials: KA
authors.lastname: White
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Kochanny
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D011517:Prothrombin Time; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020246:Venous Thrombosis / Q000188:drug therapy; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C531037:3-chloro-N-(4-chloro-2-(((5-chloro-2-pyridinyl)amino)carbonyl)-6-methoxyphenyl)-4-(((4,5-dihydro-2-oxazolyl)methylamino)methyl)-2-thiophenecarboxamide; C531036:3-chloro-N-(4-chloro-2-(((5-chloro-2-pyridinyl)amino)carbonyl)-6-methoxyphenyl)-4-((methylamino)methyl)-2-thiophenecarboxamide; D000577:Amides; D000631:Aminopyridines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D013876:Thiophenes; D062367:ortho-Aminobenzoates