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Design and synthesis of peptidomimetic factor VIIa inhibitors. 2010
Takuya Shiraishi, and
Shojiro Kadono, and
Masayuki Haramura, and
Hirofumi Kodama, and
Yoshiyuki Ono, and
Hitoshi Iikura, and
Tohru Esaki, and
Takaki Koga, and
Kunihiro Hattori, and
Yoshiaki Watanabe, and
Akihisa Sakamoto, and
Kazutaka Yoshihashi, and
Takehisa Kitazawa, and
Keiko Esaki, and
Masateru Ohta, and
Haruhiko Sato, and
Toshiro Kozono
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Japan. shiraishitky@chugai-pharm.co.jp
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.
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