title: Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.
abstract: A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.
authors.affiliation: Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, California 94804-0099, USA.
authors.forename: G
authors.initials: G
authors.lastname: Phillips
authors.forename: D D
authors.initials: DD
authors.lastname: Davey
authors.forename: K A
authors.initials: KA
authors.lastname: Eagen
authors.forename: S K
authors.initials: SK
authors.lastname: Koovakkat
authors.forename: A
authors.initials: A
authors.lastname: Liang
authors.forename: H P
authors.initials: HP
authors.lastname: Ng
authors.forename: M
authors.initials: M
authors.lastname: Pinkerton
authors.forename: L
authors.initials: L
authors.lastname: Trinh
authors.forename: M
authors.initials: M
authors.lastname: Whitlow
authors.forename: A M
authors.initials: AM
authors.lastname: Beatty
authors.forename: M M
authors.initials: MM
authors.lastname: Morrissey
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: C119211:3,3'-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy))bis(benzenecarbox(imide)amide); D000578:Amidines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; D014361:Trypsin Inhibitors; D013917:Thrombin