title: Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa.
abstract: A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
authors.affiliation: Berlex Biosciences, PO Box 4099, Richmond, CA 94804-0099, USA. Monica_Kochanny@berlex.com
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Kochanny
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Janice
authors.initials: J
authors.lastname: Ewing
authors.forename: Brian D
authors.initials: BD
authors.lastname: Griedel
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: Rushad
authors.initials: R
authors.lastname: Karanjawala
authors.forename: Wheeseong
authors.initials: W
authors.lastname: Lee
authors.forename: Dao
authors.initials: D
authors.lastname: Lentz
authors.forename: Amy M
authors.initials: AM
authors.lastname: Liang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: Gary B
authors.initials: GB
authors.lastname: Phillips
authors.forename: Joseph
authors.initials: J
authors.lastname: Post
authors.forename: Karna L
authors.initials: KL
authors.lastname: Sacchi
authors.forename: Steven T
authors.initials: ST
authors.lastname: Sakata
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Ron
authors.initials: R
authors.lastname: Vergona
authors.forename: Janette
authors.initials: J
authors.lastname: Walters
authors.forename: Kathy A
authors.initials: KA
authors.lastname: White
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Zuchun
authors.initials: Z
authors.lastname: Zhao
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Shaw
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013876:Thiophenes