Design, Synthesis and Biological Evaluation of Potent and Selective S1PR1 Agonists for the Treatment of Ulcerative Colitis  

作　　者：Huan He Mengting Xie Mengting Zhang Haiqin Zhang Huan Zhu Yuxian Fang Zihao Shen Rui Wang Zhenjiang Zhao Lili Zhu Xuhong Qian Honglin Li 

机构地区：[1]Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science&Technology,Shanghai 200237,China [2]Innovation Center for Al and Drug Discovery(ICAlDD),East China Normal University,Shanghai 200062,China

出　　处：《Chinese Journal of Chemistry》2022年第22期2625-2632,共8页中国化学（英文版）

基　　金：supported in part by the National Natural Science Foundation of China(grants 81825020 and 82150208 to H.L.);the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project(grants 21S11907900 and 20S11901000 to Z.Z.);the Fundamental Research Funds for the Central Universities.Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

摘　　要：The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease.In this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design.Among them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.

关 键 词：Ulcerativecolitis S1PR1 INFLAMMATION Drugdesign Structure-activity relationships 

分 类 号：O62[理学—有机化学]