Identification and Structure-Activity Relationship (SAR) of potent and selective oxadiazole-based agonists of sphingosine-1-phosphate receptor (S1P1)

被引：3
作者：
Liu, Tianqi [1 ,2 ]
Jin, Jing [1 ,2 ]
Chen, Yonghui [1 ,2 ]
Xi, Qiumu [2 ,3 ]
Hu, Jinping [1 ,2 ]
Jia, Wenqiang [2 ,3 ]
Chen, Xiaoguang [1 ,2 ]
Li, Yan [1 ,2 ]
Wang, Xiaojian [1 ,2 ,3 ]
Yin, Dali [1 ,2 ,3 ]
机构：
[1] Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China
[2] Chinese Acad Med Sci, Beijing 100050, Peoples R China
[3] Peking Union Med Coll, Inst Mat Med, Dept Med Chem, Beijing Key Lab Act Subst Discovery & Druggabil E, Beijing 100050, Peoples R China
来源：
BIOORGANIC CHEMISTRY | 2019年 / 82卷
基金：
北京市自然科学基金; 中国国家自然科学基金;
关键词：
S1P(1) agonist; Oxadiazole; SAR; Lymphocyte; Cascade modification; SPHINGOSINE 1-PHOSPHATE RECEPTOR; FINGOLIMOD FTY720; LYMPHOCYTE EGRESS; DISCOVERY; MODULATORS; DERIVATIVES; DRUG;
D O I：
10.1016/j.bioorg.2018.09.008
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Agonism of S1P(1) receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P(1) modulators. In this paper we described a series of oxadiazole-based S1P(1) direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P(1) receptor and favorable selectivity against S1P(3) receptor. In addition, two representative agents named 16-3b and 16-3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16-3b and the activated S1P(1) model was also studied.
引用
收藏
页码：41 / 57
页数：17
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