SAR analysis of innovative selective small molecule antagonists of sphingosine-1-phosphate 4 (S1P4) receptor
SAR analysis of innovative selective small molecule antagonists of sphingosine-1-phosphate 4 (S1P4) receptor
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DOI：
10.1016/j.bmcl.2011.06.132
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发表时间：
2011-09-15
影响因子：
2.7
通讯作者：
Roberts, Edward
中科院分区：
文献类型：
--
作者：
Urbano, Mariangela;Guerrero, Miguel;Roberts, Edward
最近的证据表明，靶向S1 P（4）受体的化学调节剂作为治疗流感病毒感染的新型机制药物的创新应用。S1 P（4）受体的调节也可能代表反应性血小板增多是不期望的效应或需要增加巨核细胞生成的临床病症的替代治疗方法。除了我们最近的研究计划披露，我们不知道任何选择性S1 P（4）拮抗剂在文献中报道的日期。在此，我们描述了高通量筛选（HTS）衍生的命中5-（2，5-二氯苯基）-N-（2，6-二甲基苯基）呋喃-2-甲酰胺及其2，5-二甲基苯基类似物的互补结构-活性关系（SAR）。呋喃环的系统性结构修饰表明，该区域的空间和电子因素对效力有显着影响。呋喃部分被成功地替换为噻吩或苯环，保持在低纳摩尔范围内的效力和对其他S1 P受体亚型的高选择性。通过扩大命中衍生类内的分子多样性，我们的SAR研究提供了创新的小分子强效和选择性S1 P（4）拮抗剂，适用于靶受体的体内药理学验证。(C)2011爱思唯尔有限公司保留所有权利。
Recent evidence suggests an innovative application of chemical modulators targeting the S1P(4) receptor as novel mechanism-based drugs for the treatment of influenza virus infection. Modulation of the S1P(4) receptor may also represent an alternative therapeutic approach for clinical conditions where reactive thrombocytosis is an undesired effect or increased megakaryopoiesis is required. With the exception of our recent research program disclosure, we are not aware of any selective S1P(4) antagonists reported in the literature to date. Herein, we describe complementary structure-activity relationships (SAR) of the high-throughput screening (HTS)-derived hit 5-(2,5-dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide and its 2,5-dimethylphenyl analog. Systematic structural modifications of the furan ring showed that both steric and electronic factors in this region have a significant impact on the potency. The furan moiety was successfully replaced with a thiophene or phenyl ring maintaining potency in the low nanomolar range and high selectivity against the other S1P receptor subtypes. By expanding the molecular diversity within the hit-derived class, our SAR study provides innovative small molecule potent and selective S1P(4) antagonists suitable for in vivo pharmacological validation of the target receptor. (C) 2011 Elsevier Ltd. All rights reserved.