Taylor Simon, Gray James R J, Willis Robert, Deeks Nigel, Haynes Andrea, Campbell Colin, Gaskin Pam, Leavens Karen, Demont Emmanuel, Dowell Simon, Cryan Jenni, Morse Mary, Patel Aarti, Garden Helen, Witherington Jason
Immuno-Inflammation Center of Excellence for Drug Discovery , GlaxoSmithKline, Stevenage, UK.
Xenobiotica. 2012 Jul;42(7):671-86. doi: 10.3109/00498254.2011.645908. Epub 2012 Jan 9.
Sphingosine-1-phosphate (S1P(1)) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia. Using an integrated pharmacokinetic/pharmacodynamic (PK-PD) approach based on an in vivo rat model, novel S1P(1) agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod. The in vivo potency of 15 compounds based on PK-PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P(1) receptor using β arrestin recruitment and G-protein signalling. A structurally novel S1P(1) agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.
鞘氨醇-1-磷酸（S1P(1)）受体激动剂，如芬戈莫德（FTY-720），是一类新型免疫调节剂，在复发缓解型多发性硬化症的治疗中具有临床应用价值。这类化合物通过诱导外周淋巴细胞减少发挥作用。基于体内大鼠模型采用综合药代动力学/药效学（PK-PD）方法，鉴定出了新型S1P(1)激动剂，与芬戈莫德相比，预计其在人体内使淋巴细胞减少的可逆速度更快。基于大鼠淋巴细胞减少模型的PK-PD建模，对15种化合物的体内效力与使用β-arrestin募集和G蛋白信号传导在S1P(1)受体处的体外效力测量值进行了相关性分析。鉴定出了一种结构新颖的S1P(1)激动剂，并给出了人体药代动力学和临床剂量的预测。
