Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination.
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.
Shiraishi
Takuya
T
Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. shiraishitky@chugai-pharm.co.jp
Kadono
Shojiro
S
Haramura
Masayuki
M
Kodama
Hirofumi
H
Ono
Yoshiyuki
Y
Iikura
Hitoshi
H
Esaki
Tohru
T
Koga
Takaki
T
Hattori
Kunihiro
K
Watanabe
Yoshiaki
Y
Sakamoto
Akihisa
A
Yoshihashi
Kazutaka
K
Kitazawa
Takehisa
T
Esaki
Keiko
K
Ohta
Masateru
M
Sato
Haruhiko
H
Kozono
Toshiro
T
D001777:Blood Coagulation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013923:Thromboembolism / Q000188:drug therapy* / Q000201:enzymology
D010455:Peptides; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D015942:Factor VIIa