Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, United States.
Bioorg Med Chem Lett. 2012 Jan 1;22(1):537-42. doi: 10.1016/j.bmcl.2011.10.096. Epub 2011 Nov 4.
High affinity and selective small molecule agonists of the S1P(4) receptor (S1P(4)-R) may have significant therapeutic utility in diverse disease areas including autoimmune diseases, viral infections and thrombocytopenia. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 3-(2-(2,4-dichlorophenoxy)ethoxy)-6-methyl-2-nitropyridine as a moderately potent and selective S1P(4)-R hit agonist. Design, synthesis and systematic structure-activity relationships study of the HTS-derived hit led to the development of novel potent S1P(4)-R agonists exquisitely selective over the remaining S1P(1-3,5)-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R.
高亲和力和选择性的 S1P(4)受体（S1P(4)-R）小分子激动剂在多种疾病领域具有重要的治疗应用价值，包括自身免疫性疾病、病毒感染和血小板减少症。高通量筛选（HTS）从分子文库-小分子库中鉴定出 3-(2-(2,4-二氯苯氧基)乙氧基)-6-甲基-2-硝基吡啶是一种具有中等效力和选择性的 S1P(4)-R 激动剂。对 HTS 衍生的命中化合物进行设计、合成和系统的构效关系研究，开发出新型强效 S1P(4)-R 激动剂，对其余的 S1P(1-3,5)-R 家族成员具有极高的选择性。值得注意的是，本文报道的分子为破译 S1P(4)-R 的生物学功能和评估其治疗应用提供了新的药理学工具。
