title: Discovery of novel 1,2,4-thiadiazole derivatives as potent, orally active agonists of sphingosine 1-phosphate receptor subtype 1 (S1P(1)).
abstract: A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.
authors.affiliation: GlaxoSmithKline, R&D China, No. 3 Building, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PRC.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Guanghui
authors.initials: G
authors.lastname: Deng
authors.forename: Hailong
authors.initials: H
authors.lastname: Wang
authors.forename: Linbo
authors.initials: L
authors.lastname: Luan
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Meng
authors.forename: Qiongfeng
authors.initials: Q
authors.lastname: Xu
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.forename: Xuesong
authors.initials: X
authors.lastname: Xu
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Baowei
authors.initials: B
authors.lastname: Zhao
authors.forename: Chengyong
authors.initials: C
authors.lastname: Li
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Guo
authors.forename: Jiansong
authors.initials: J
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qiantao
authors.initials: Q
authors.lastname: Jia
authors.forename: Hongtao
authors.initials: H
authors.lastname: Lu
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Xiang
authors.forename: John D
authors.initials: JD
authors.lastname: Elliott
authors.forename: Xichen
authors.initials: X
authors.lastname: Lin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D013830:Thiadiazoles