Design and Synthesis of Peptidomimetic Factor VIIa Inhibitors

被引：2

作者：

Shiraishi, Takuya ^{[1
]}

Kadono, Shojiro ^{[1
]}

Haramura, Masayuki ^{[1
]}

Kodama, Hirofumi ^{[1
]}

Ono, Yoshiyuki ^{[1
]}

Iikura, Hitoshi ^{[1
]}

Esaki, Tohru ^{[1
]}

Koga, Takaki ^{[1
]}

Hattori, Kunihiro ^{[1
]}

Watanabe, Yoshiaki ^{[1
]}

Sakamoto, Akihisa ^{[1
]}

Yoshihashi, Kazutaka ^{[1
]}

Kitazawa, Takehisa ^{[1
]}

Esaki, Keiko ^{[1
]}

Ohta, Masateru ^{[1
]}

Sato, Haruhiko ^{[1
]}

Kozono, Toshiro ^{[1
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Fuji Gotemba Res Labs, Shizuoka 4128513, Japan

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2010年 / 58卷 / 01期

关键词：

factor VIIa; X-ray; 2Xactivated partial thromboplastin time/2Xprothrombin time; thromboembolic disorder; peptidomimetic inhibitor; FACTOR-VIIA/TISSUE-FACTOR; COAGULATION-FACTOR VIIA; TISSUE FACTOR MUTANT; CRYSTAL-STRUCTURE; P3; MOIETIES; FACTOR XA; COMPLEX; THROMBOSIS; OPTIMIZATION; EFFICACY;

D O I：

10.1248/cpb.58.38

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Selective factor Vila-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.

引用

页码：38 / 44

页数：7

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