Structural modification of an orally active thrombin inhibitor, LB30057: Replacement of the D-pocket-binding naphthyl moiety

被引：30

作者：

Lee, K ^{[1
]}

Hwang, SY ^{[1
]}

Hong, S ^{[1
]}

Hong, CY ^{[1
]}

Lee, CS ^{[1
]}

Shin, Y ^{[1
]}

Kim, S ^{[1
]}

Yun, M ^{[1
]}

Yoo, YJ ^{[1
]}

Kang, M ^{[1
]}

Oh, YS ^{[1
]}

机构：

[1] LG Chem Ltd, Biotech Res Inst, Taejon 305380, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 1998年 / 6卷 / 06期

关键词：

thrombin; inhibitor; oral; selective; amidrazone;

D O I：

10.1016/S0968-0896(98)00044-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (K-i = 0.38 nM), selective, and orally active thrombin inhibitor. As a continuation of studies into benzamidrazone-based thrombin inhibitors, we have structurally modified compound 2 by replacing the naphthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin and oral absorption. The highest activity was obtained with compound 23 (K-i = 0.045 nM). (C) 1998 Elsevier Science Ltd. All rights reserved.

引用

页码：869 / 876

页数：8

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