Removal of Sphingosine 1-Phosphate Receptor-3 (S1P3) Agonism is Essential, But Inadequate to Obtain Immunomodulating 2-Aminopropane-1,3-diol S1P1 Agonists with Reduced Effect on

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• 作者：Maiko Hamada ; Mitsuharu Nakamura ; Masatoshi Kiuchi ; Kaoru Marukawa ; Ayumi Tomatsu ; Kyoko Shimano ; Noriko Sato ; Kunio Sugahara ; Mahoko Asayama ; Kan Takagi ; Kunitomo Adachi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 22, 2010
• 年：2010
• 卷：53
• 期：8
• 页码：3154-3168
• 全文大小：1016K
• 年卷期：v.53,no.8(April 22, 2010)
• ISSN：1520-4804

文摘

A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P₁) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P₁ but no agonism at S1P₃, which had been reported to be a receptor responsible for heart rate reduction. Although high S1P₁/S1P₃ selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P₃ agonism should be responsible for the heart rate reduction caused by S1P₁ agonists. Only 2-amino-2-[2-[2′-fluoro-4′-(4-methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P₁ receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.