Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors

被引：55

作者：

Gomtsyan, A ^{[1
]}

Didomenico, S ^{[1
]}

Lee, CH ^{[1
]}

Matulenko, MA ^{[1
]}

Kim, K ^{[1
]}

Kowaluk, EA ^{[1
]}

Wismer, CT ^{[1
]}

Mikusa, J ^{[1
]}

Yu, HX ^{[1
]}

Kohlhaas, K ^{[1
]}

Jarvis, MF ^{[1
]}

Bhagwat, SS ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Prod Div, Neurosci Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 17期

关键词：

D O I：

10.1021/jm020049a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.

引用

页码：3639 / 3648

页数：10

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