Discovery of Clinical Candidate GSK1842799 As a Selective S1P₁ Receptor Agonist (Prodrug) for Multiple Sclerosis

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 (<i>S</i>)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)­phenyl)-1,3,4-thiadiazol-2-yl)­propan-1-ol (<b>10</b>, GSK1842799). Upon phosphorylation, the compound (<b>10</b>-P) showed subnanomole S1P₁ agonist activity with >1000× selectivity over S1P₃. The alcohol <b>10</b> demonstrated good oral bioavailability and rapid in vivo conversion to <b>10</b>-P. Dosed orally at 0.1 mg/kg, <b>10</b> significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, <b>10</b> 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 <b>10</b> 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 <b>10</b> (GSK1842799) was selected as a candidate for further clinical development