2. Academic Validation
  3. Discovery of oxazole and triazole derivatives as potent and selective S1P(1) agonists through pharmacophore-guided design

Discovery of oxazole and triazole derivatives as potent and selective S1P(1) agonists through pharmacophore-guided design

  • Eur J Med Chem. 2014 Oct 6:85:1-15. doi: 10.1016/j.ejmech.2014.07.081.
Yulin Tian 1,  Jing Jin 2,  Xiaojian Wang 3,  Jinping Hu 2,  Qiong Xiao 4,  Wanqi Zhou 2,  Xiaoguang Chen 2,  Dali Yin 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 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.
PMID: 25072873 DOI: 10.1016/j.ejmech.2014.07.081
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.

Keywords

Immunomodulator; Lymphocyte; Pharmacophore; Prodrug; S1P(1) agonist.

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