Discovery of Novel 1,2,4-Thiadiazole Derivatives as Potent, Orally Active Agonists of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P(1))

作者：Ren Feng; Deng Guanghui; Wang Hailong; Luan Linbo; Meng Qinghua; Xu Qiongfeng; Xu Heng; Xu Xuesong; Zhang Haibo; Zhao Baowei; Li Chengyong; Guo Taylor B; Yang Jiansong; Zhang Wei; Zhao Yonggang; Jia Qiantao; Lu Hongtao; Xiang Jia Ning; Elliott John D; Lin Xichen^*

来源：Journal of Medicinal Chemistry, 2012, 55(9): 4286-4296.

DOI：10.1021/jm2016107

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.

• 出版日期2012-5-10