Design and synthesis of peptidomimetic factor VIIa inhibitors.
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.
Shiraishi
Takuya
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 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
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
D010455:Peptides; D013925:Thromboplastin; D015942:Factor VIIa