title: Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif.
abstract: 2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Kreutter
authors.forename: Tianbao
authors.initials: T
authors.lastname: Lu
authors.forename: Lily
authors.initials: L
authors.lastname: Lee
authors.forename: Edward C
authors.initials: EC
authors.lastname: Giardino
authors.forename: Sharmila
authors.initials: S
authors.lastname: Patel
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Guozhang
authors.initials: G
authors.lastname: Xu
authors.forename: Mark
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Haertlein
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Mohan
authors.forename: Carl
authors.initials: C
authors.lastname: Crysler
authors.forename: Stephen
authors.initials: S
authors.lastname: Eisennagel
authors.forename: Malini
authors.initials: M
authors.lastname: Dasgupta
authors.forename: Martin
authors.initials: M
authors.lastname: McMillan
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: Norman D
authors.initials: ND
authors.lastname: Huebert
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D020816:Amino Acid Motifs; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001665:Binding Sites; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D000882:Haplorhini; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: C529907:2-cyano-6-fluorophenylacetamide; D000081:Acetamides; D000925:Anticoagulants; D009570:Nitriles; D013917:Thrombin