Optimization of a coagulation factor VIIa inhibitor found in factor Xa inhibitor library.
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.
Sagi
Kazuyuki
K
Pharmaceutical Research Laboratories, Ajinomoto Company Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi 210-8681, Japan. kazuyuki_sagi@ajinomoto.com
Fujita
Koichi
K
Sugiki
Masayuki
M
Takahashi
Mitsuo
M
Takehana
Shunji
S
Tashiro
Kazumi
K
Kayahara
Takashi
T
Yamanashi
Masahiro
M
Fukuda
Yumiko
Y
Oono
Seiji
S
Okajima
Akiko
A
Iwata
Seinosuke
S
Shoji
Masataka
M
Sakurai
Kuniya
K
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
D000991:Antithrombins; D015842:Serine Proteinase Inhibitors; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa