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Eur J Med Chem. 2014 Oct 6;85:1-15. doi: 10.1016/j.ejmech.2014.07.081. Epub 2014 Jul 24.

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

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  • 1State 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.
  • 2State 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.
  • 3State 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.
  • 4Department 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.
  • 5State 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.

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.

Copyright © 2014 Elsevier Masson SAS. All rights reserved.

KEYWORDS:

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

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