Pennington Lewis D, Sham Kelvin K C, Pickrell Alexander J, Harrington Paul E, Frohn Michael J, Lanman Brian A, Reed Anthony B, Croghan Michael D, Lee Matthew R, Xu Han, McElvain Michele, Xu Yang, Zhang Xuxia, Fiorino Michael, Horner Michelle, Morrison Henry G, Arnett Heather A, Fotsch Christopher, Wong Min, Cee Victor J
Medicinal Chemistry, Molecular Structure, HTS and Molecular Pharmacology, Inflammation Research, Pharmacokinetics and Drug Metabolism, Toxicology, and Pharmaceutics, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
ACS Med Chem Lett. 2011 Jul 29;2(10):752-7. doi: 10.1021/ml2001399. eCollection 2011 Oct 13.
The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.035 μM, 96% efficacy) and the >100-fold selectivity that it displays against receptor subtypes S1P2-5 suggest that it may serve as a valuable tool to understand the clinical relevance of selective S1P1 agonism.
鞘氨醇-1-磷酸-1受体（S1P1）及其内源性配体鞘氨醇-1-磷酸（S1P）协同调节淋巴细胞从淋巴系统的运输。在此，我们披露了4-甲氧基-N-[2-(三氟甲基)联苯-4-基氨基甲酰基]烟酰胺（8），这是一种罕见的缺乏极性头基团的合成S1P1激动剂实例，在大鼠单次口服剂量（1 mg/kg）24小时后，它能使循环淋巴细胞显著减少（POC = -78%）。8对S1P1表现出的优异效力（EC50 = 0.035 μM，96%效能）以及它对受体亚型S1P2 - 5显示出的>100倍选择性表明，它可能作为一种有价值的工具来理解选择性S1P1激动作用的临床相关性。
