title: Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination.
abstract: 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.
authors.affiliation: Fuji Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. shiraishitky@chugai-pharm.co.jp
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Shojiro
authors.initials: S
authors.lastname: Kadono
authors.forename: Masayuki
authors.initials: M
authors.lastname: Haramura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iikura
authors.forename: Tohru
authors.initials: T
authors.lastname: Esaki
authors.forename: Takaki
authors.initials: T
authors.lastname: Koga
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshihashi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Esaki
authors.forename: Masateru
authors.initials: M
authors.lastname: Ohta
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kozono
mesh_terms: 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
chemical_list: D010455:Peptides; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D015942:Factor VIIa