title: Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2,6-diphenoxypyridines.
abstract: A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.
authors.affiliation: Pharmaceuticals Research, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, Richmond, CA 94804-0099, USA.
authors.forename: Howard P
authors.initials: HP
authors.lastname: Ng
authors.forename: Brad O
authors.initials: BO
authors.lastname: Buckman
authors.forename: Keith A
authors.initials: KA
authors.lastname: Eagen
authors.forename: William J
authors.initials: WJ
authors.lastname: Guilford
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Kochanny
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: Shung C
authors.initials: SC
authors.lastname: Wu
authors.forename: Dao
authors.initials: D
authors.lastname: Lentz
authors.forename: Amy
authors.initials: A
authors.lastname: Liang
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: David
authors.initials: D
authors.lastname: Smith
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: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: Gary B
authors.initials: GB
authors.lastname: Phillips
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002417:Cattle; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011725:Pyridines; D015842:Serine Proteinase Inhibitors