title: Optimization of a coagulation factor VIIa inhibitor found in factor Xa inhibitor library.
abstract: An inhibitor of the complex of factor VIIa and tissue factor (fVIIa/TF), 2-substituted-4-amidinophenylpyruvic acid 1a, was structurally modified with the aim of increasing its potency and selectivity. The lead compound 1a was originally found in our factor Xa (fXa) inhibitor library on the basis of structural similarity of the primary binding sites of fVIIa and fXa. The design was based on computational docking studies using the extracted active site of fVIIa. Compound 1j was found to inhibit factor VIIa/TF at nanomolar concentration with improved selectivity versus fXa and thrombin and it preferentially prolonged the clotting time in the TF-dependent extrinsic pathway.
authors.affiliation: Pharmaceutical Research Laboratories, Ajinomoto Company Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan. kazuyuki_sagi@ajinomoto.com
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sagi
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sugiki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Takahashi
authors.forename: Shunji
authors.initials: S
authors.lastname: Takehana
authors.forename: Kazumi
authors.initials: K
authors.lastname: Tashiro
authors.forename: Takashi
authors.initials: T
authors.lastname: Kayahara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamanashi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Seiji
authors.initials: S
authors.lastname: Oono
authors.forename: Akiko
authors.initials: A
authors.lastname: Okajima
authors.forename: Seinosuke
authors.initials: S
authors.lastname: Iwata
authors.forename: Masataka
authors.initials: M
authors.lastname: Shoji
authors.forename: Kuniya
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D015951:Factor Xa / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013925:Thromboplastin / Q000037:antagonists & inhibitors
chemical_list: D000991:Antithrombins; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa