title: Discovery of oxazole and triazole derivatives as potent and selective S1P(1) agonists through pharmacophore-guided design.
abstract: We have discovered a series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives as potent and selective S1P1 agonists (prodrugs) based on pharmacophore-guided rational design. Most compounds showed high affinity and selectivity for S1P1 receptor. Compounds 19b, 19d and 19p displayed clear dose responsiveness in the lymphocyte reduction model when administered orally at doses of 0.3, 1.0, 3.0 mg/kg with reduced effect on heart rate. These three compounds were also identified to have favorable pharmacokinetic properties.
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Yulin
authors: Y
authors: Tian
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Jing
authors: J
authors: Jin
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: wangxiaojian@imm.ac.cn.
authors: Xiaojian
authors: X
authors: Wang
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Jinping
authors: J
authors: Hu
authors: Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Qiong
authors: Q
authors: Xiao
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Wanqi
authors: W
authors: Zhou
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Xiaoguang
authors: X
authors: Chen
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: yindali@imm.ac.cn.
authors: Dali
authors: D
authors: Yin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006339:Heart Rate / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D010080:Oxazoles; D049349:Receptors, Lysosphingolipid; D014230:Triazoles
keywords: Immunomodulator; Lymphocyte; Pharmacophore; Prodrug; S1P(1) agonist