Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Design and Synthesis of Peptidomimetic Factor VIIa Inhibitors
Takuya ShiraishiShojiro KadonoMasayuki HaramuraHirofumi KodamaYoshiyuki OnoHitoshi IikuraTohru EsakiTakaki KogaKunihiro HattoriYoshiaki WatanabeAkihisa SakamotoKazutaka YoshihashiTakehisa KitazawaKeiko EsakiMasateru OhtaHaruhiko SatoToshiro Kozono
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2010 Volume 58 Issue 1 Pages 38-44

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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.

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© 2010 The Pharmaceutical Society of Japan
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