Demont Emmanuel H, Andrews Benjamin I, Bit Rino A, Campbell Colin A, Cooke Jason W B, Deeks Nigel, Desai Sapna, Dowell Simon J, Gaskin Pam, Gray James R J, Haynes Andrea, Holmes Duncan S, Kumar Umesh, Morse Mary A, Osborne Greg J, Panchal Terry, Patel Bela, Perboni Alcide, Taylor Simon, Watson Robert, Witherington Jason, Willis Robert
Immuno Inflammation Center of Excellence for Drug Discovery and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom.
ACS Med Chem Lett. 2011 Mar 24;2(6):444-9. doi: 10.1021/ml2000214. eCollection 2011 Jun 9.
Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.
捷灵亚（芬戈莫德，FTY720）最近获得美国食品药品监督管理局（FDA）批准，用于治疗复发缓解型多发性硬化症（RRMS）患者。它是五种1-磷酸鞘氨醇（S1P）G蛋白偶联受体（S1P1和S1P3 - 5）中四种的强效激动剂。据推测，芬戈莫德的疗效归因于S1P1激动作用，而其心血管副作用（短暂性心动过缓和高血压）则归因于S1P3激动作用。我们发现了一系列选择性S1P1激动剂，其中包括3 - [6 -（5 - {3 - 氰基 - 4 - [（1 - 甲基乙基）氧基]苯基}-1,2,4 - 恶二唑 - 3 - 基）-5 - 甲基 - 3,4 - 二氢 - 2（1H）-异喹啉基]丙酸酯（化合物20），这是一种强效、不作用于S1P3且口服有效的S1P1激动剂。在胶原诱导的关节炎模型中，化合物20与芬戈莫德疗效相当，并且在临床前显示出优异的药代动力学特性。重要的是，化合物20对S1P3的选择性导致在遥测大鼠中即使高剂量水平也没有心血管信号。
