To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P₁ modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P₁ agonist activity with >1000× selectivity over S1P₃. The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.

中文翻译：

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发现临床候选 GSK1842799 作为多发性硬化症的选择性 S1P1 受体激动剂（前药）

为了开发多发性硬化症 (MS) 的有效口服治疗方法，我们发现了一系列烷基取代的联芳氨基醇作为选择性 S1P ₁调节剂。一个例子是 ( S )-2-氨基-2-(5-(4-(辛氧基)-3-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)丙-1-醇( 10 , GSK1842799)。磷酸化后，化合物 ( 10 -P) 显示出亚纳摩尔 S1P ₁激动剂活性，选择性超过 S1P ₃ 1000 倍。酒精10表现出良好的口服生物利用度和快速的体内转化为10 -P。以 0.1 mg/kg 口服给药，给药后 6 小时显着降低血液淋巴细胞计数10，在 3 mg/kg 时，10在 MS 的小鼠 EAE 模型中达到了与 FTY720 相当的功效。对食蟹猴的进一步药代动力学/药效学 (PK/PD) 研究表明，口服10 剂3.8 mg/kg 后，活性磷酸盐达到血浆水平，与人类临床试验中显示的 FTY-720 磷酸盐 (FTY-P) 相当药代动力学研究。基于良好的体外 ADME 和体内 PK/PD 特性以及广泛的毒理学评估，化合物10（GSK1842799）被选为进一步临床开发的候选物。