1,4-cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma
1,4-cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma
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DOI：
10.1021/jm970090r
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发表时间：
1998-03-12
影响因子：
7.3
通讯作者：
Torphy, TJ
中科院分区：
文献类型：
--
作者：
Christensen, SB;Guider, A;Torphy, TJ
在一系列细胞和体内测定中对多种 PDE4 抑制剂的评估提出了一种提高 PDE4 抑制剂治疗指数的策略，即通过提高其抑制 PDE4 催化活性的能力与竞争中枢神经系统中高亲和力 [H-3]咯利普兰结合位点的能力的选择性。使用该策略最终鉴定出 cis-4-cyano-4-[3-(环戊氧基)-4-甲氧基苯基]环己烷-1-羧酸 (1, SB 207499, Ariflo(TM))，它是一种有效的第二代 PDE4 抑制剂，与原型第一代抑制剂 (R)-咯利普兰相比，其副作用可能性较低。
Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [H-3]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1 -carboxylic acid (1, SB 207499, Ariflo(TM)), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.