74 research outputs found
Discovery of Clinical Candidate GSK1842799 As a Selective S1P<sub>1</sub> 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 S1P<sub>1</sub> 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 S1P<sub>1</sub> agonist activity
with >1000× selectivity over S1P<sub>3</sub>. 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
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