Structure-activity studies on diphenylpyrazine derivatives: A novel class of prostacyclin receptor agonists

被引：41

作者：

Asaki, Tetsuo ^{[1
]}

Hamamoto, Taisuke ^{[1
]}

Sugiyama, Yukiteru ^{[1
]}

Kuwano, Keiichi ^{[1
]}

Kuwabara, Kenji ^{[1
]}

机构：

[1] Nippon Shinyaku Co Ltd, Discovery Res Labs, Minami Ku, Kyoto 6018550, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 21期

关键词：

prostacyclin; IP receptor agonist; diphenylpyrazine; anti-aggreatory; activity;

D O I：

10.1016/j.bmc.2007.08.010

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：

To develop nonprostanoid prostacyclin receptor agonists with a high degree of metabolic resistance and an extended duration of action, a novel series of diphenylpyrazine derivatives was synthesized and evaluated for their inhibition of ADP-induced human platelet aggregation. Structure-activity relationship studies on the side chain containing the carboxylic acid moiety of the lead compound 5c showed that the length of the linker and the presence of the concatenating nitrogen atom adjacent to the pyrazine ring are critical for the antiaggregatory activity. This study led to the discovery of 2-amino-5,6-diphenylpyrazine derivatives 8c, 15a, and 15b. which showed potent inhibition of platelet aggregation with IC50 values of 0.2 mu M. Among these compounds, 15b is an orally available and long-lasting prostacyclin receptor agonist which is promising for the treatment of various vascular diseases. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：6692 / 6704

页数：13

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