title: Design and synthesis of peptidomimetic factor VIIa inhibitors.
abstract: Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 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: D032701:Biomimetics; D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D010455:Peptides; D013925:Thromboplastin; D015942:Factor VIIa