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Syl948是通过化学合成获得的一种全新结构的选择性鞘氨醇-1-磷酸1型受体(sphingosine-1-phosphate receptor 1,S1P1)前药类激动剂。体外HTRF-IP1(homogeneous time-resolved fluorescence-IP1)检测显示,其活性磷酸酯形式Syl948-P对S1P1具有较强的激动活性[EC50:(83±16)nmol·L-1],而对S1P3激动作用较弱[EC50:(1 026±90)nmol·L-1],表明其具有良好的受体激动选择性。体内生物活性研究表明,单次灌胃给予SD大鼠Syl948(10 mg·kg-1)能够显著降低动物外周血淋巴细胞水平,最大淋巴细胞降低百分率为63%,与相同剂量的阳性药芬戈莫德(fingolimod,FTY720)作用强度相当(以克分子剂量比较)。单次灌胃给予SD大鼠Syl948(10 mg·kg-1),对大鼠心率没有明显影响,优于阳性药FTY720。每天灌胃给予小鼠Syl948(2或4 mg·kg-1)能够显著延长小鼠皮肤移植模型中移植皮片的存活时间。上述研究结果提示,Syl948具有较强的抗皮肤移植排斥反应活性,且无减缓心率的不良反应。
Syl948 is a brand new structure-selective sphingosine-1-phosphate receptor 1 (S1P1) prodrug agonist obtained by chemical synthesis. In vitro HTRF-IP1 assay showed that the active phosphate ester form Syl948-P had strong agonistic activity on S1P1 [EC50: (83 ± 16) nmol·L-1] Weak agitation [EC50: (1026 ± 90) nmol·L-1], indicating that it has good receptor agonistic selectivity. In vivo biological activity studies showed that single intragastric administration of Syl948 (10 mg · kg-1) to SD rats significantly reduced the level of peripheral blood lymphocytes in animals, the maximum percentage of lymphocytes decreased 63%, with the same dose of positive drug Fingo Moderate (fingolimod, FTY720) Intensity (equivalent to the molar dose comparison). Single intragastric administration of Syl948 (10 mg · kg-1) to SD rats had no significant effect on heart rate in rats, which was superior to that of FTY720. Daily oral administration of Syl948 (2 or 4 mg · kg-1) significantly prolonged graft survival in mouse skin graft models. The above results suggest that Syl948 has strong resistance to skin allograft rejection without adverse effects of slowing heart rate.