title: Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Sylvie G
authors.initials: SG
authors.lastname: Bernier
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Doyle
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Lorusso
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Morgan
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
authors.affiliation: Department of Medicinal Chemistry and Department of Preclinical Research, Praecis Pharmaceuticals Incorporated , 830 Winter Street, Waltham, Massachusetts 02451, United States.
authors.forename: Ghotas
authors.initials: G
authors.lastname: Evindar
keywords: S1P1 modulator; biaryl aminoalcohol; mouse EAE model; multiple sclerosis; prodrug