Discovery of Novel 1,2,4-Thiadiazole Derivatives as Potent, Orally Active Agonists of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P1)

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• 作者：Feng Ren ; Guanghui Deng ; Hailong Wang ; Linbo Luan ; Qinghua Meng ; Qiongfeng Xu ; Heng Xu ; Xuesong Xu ; Haibo Zhang ; Baowei Zhao ; Chengyong Li ; Taylor B. Guo ; Jiansong Yang ; Wei Zhang ; Yonggang Zhao ; Qiantao Jia ; Hongtao Lu ; Jia-Ning Xiang ; John D. Elliott ; Xichen Lin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4286-4296
• 全文大小：476K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P₁ agonists. The extensive structure鈥揳ctivity 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.