发现3-芳基丙酸是鞘氨醇-1-磷酸受体-1（S1P1）的强效激动剂，对所有其他已知的S1P受体亚型具有高选择性。
Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.
作者信息
Yan Lin, Huo Pei, Doherty George, Toth Lesile, Hale Jeffrey J, Mills Sander G, Hajdu Richard, Keohane Carol A, Rosenbach Mark J, Milligan James A, Shei Gan-Ju, Chrebet Gary, Bergstrom James, Card Deborah, Quackenbush Elizabeth, Wickham Alexandra, Mandala Suzanne M
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
出版信息
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3679-83. doi: 10.1016/j.bmcl.2006.04.084. Epub 2006 May 11.
A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.
合成了一系列3-芳基丙酸作为S1P1受体激动剂。对侧链苯环的构效关系研究揭示了几个结构特征，这些特征提供了S1P1与S1P2 - 5结合的选择性。这些高选择性的S1P1激动剂可诱导小鼠外周血淋巴细胞减少，其中一种在大鼠皮肤移植模型中被发现有效，这支持了S1P1激动作用是临床前动物模型中观察到的免疫抑制功效的主要原因。
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