Design of benzamidine-type inhibitors of factor Xa

被引：39

作者：

Gabriel, B

Stubbs, MT

Bergner, A

Hauptmann, J

Bode, W

Stürzebecher, J

Moroder, L

机构：

[1] Max Planck Inst Biochem, D-82152 Martinsried, Germany

[2] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany

[3] Univ Jena, Zentrum Vaskulare Biol & Med, D-99089 Erfurt, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 22期

关键词：

D O I：

10.1021/jm980227t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of derivatives of rac-benzenesulfonyl-glycyl-phenylalanine or its ethyl ester with a combination of thioamido/amidino or amidino/amidino substituents in the benzene rings was synthesized as potential inhibitors of factor Xa (Ma). Among these, the racemic 4'-amidinobenzenesulfonyl-glycyl-4-amidinophenylalanine ethyl ester was found to exhibit the highest affinity for fXa despite the unfavored location of the amidino substituent in the para position. X-ray structural analysis of the trypsin complex with this bis-benzamidine compound revealed a retro-binding mode if compared to those of similar compounds, so far analyzed in complexes with trypsin or fXa. This noncanonical binding mode as well as its slow plasma clearance rates in rats, if compared to those of other benzamidine derivatives, suggests this compound as an interesting new lead structure for the design of fXa inhibitors.

引用

页码：4240 / 4250

页数：11

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