Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
J Med Chem. 2010 Apr 22;53(8):3154-68. doi: 10.1021/jm901776q.
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 (S1P(1)) 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 S1P(1) but no agonism at S1P(3), which had been reported to be a receptor responsible for heart rate reduction. Although high S1P(1)/S1P(3) 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 S1P(3) agonism should be responsible for the heart rate reduction caused by S1P(1) 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 S1P(1) 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.
一系列具有联苯部分的 2-取代 2-氨基丙烷-1,3-二醇及其磷酸盐被合成，以获得具有强大免疫调节活性的鞘氨醇 1-磷酸受体-1（S1P(1)）受体激动剂，同时对心率几乎没有影响。许多合成的化合物可充分减少外周血淋巴细胞的数量。一些磷酸酯在 S1P(1) 上具有很强的激动作用，但在 S1P(3) 上没有激动作用，S1P(3) 已被报道为一种负责降低心率的受体。虽然高 S1P(1)/S1P(3)选择性被认为有利于降低对心率的影响，但几乎所有的磷酸酯在体内都显示出显著的降低心率作用。结果表明，除了 S1P(3)激动作用外，其他因素也可能导致 S1P(1)激动剂引起的心率降低。只有 2-氨基-2-[2-[2'-氟-4'-(4-甲基苯基硫基)联苯-4-基]乙基]丙烷-1,3-二醇（6d）被鉴定为具有免疫调节活性和降低心率作用的理想 S1P(1)受体激动剂，这是通过使用体内评价系统进行的独特筛选流程确定的。
