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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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posted on 2012-05-10, 00:00 authored by 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
A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P1 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 (Fu > 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.

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    Journal of Medicinal Chemistry

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