鞘氨醇-1-磷酸1（S1P1）受体的高选择性强效激动剂。
Highly selective and potent agonists of sphingosine-1-phosphate 1 (S1P1) receptor.
作者信息
Vachal Petr, Toth Leslie M, Hale Jeffrey J, Yan Lin, Mills Sander G, Chrebet Gary L, Koehane Carol A, Hajdu Richard, Milligan James A, Rosenbach Mark J, Mandala Suzanne
机构信息
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
出版信息
Bioorg Med Chem Lett. 2006 Jul 15;16(14):3684-7. doi: 10.1016/j.bmcl.2006.04.064. Epub 2006 May 6.
Novel series of sphingosine-1-phosphate (S1P) receptor agonists were developed through a systematic SAR aimed to achieve high selectivity for a single member of the S1P family of receptors, S1P1. The optimized structure represents a highly S1P1-selective and efficacious agonist: S1P1/S1P2, S1P1/S1P3, S1P1/S1P4>10,000-fold, S1P1/S1P5>600-fold, while EC50 (S1P1) <0.2 nM. In vivo experiments are consistent with S1P1 receptor agonism alone being sufficient for achieving desired lymphocyte-lowering effect.
通过系统的构效关系研究，开发出了一系列新型的1-磷酸鞘氨醇（S1P）受体激动剂，旨在对S1P受体家族的单个成员S1P1实现高选择性。优化后的结构代表了一种高度S1P1选择性且有效的激动剂：S1P1/S1P2、S1P1/S1P3、S1P1/S1P4大于10000倍，S1P1/S1P5大于600倍，而EC50（S1P1）<0.2 nM。体内实验表明，仅S1P1受体激动就足以实现所需的降低淋巴细胞的效果。
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