Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity

Jin Cai, Ligang Liu, Kwon Ho Hong, Peng Wang, Lushen Li, Meng Cao, Chunlong Sun, Xiaoqing Wu, Xi Zong, Junqing Chen, Min Ji

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

A series of phenoxybutanoic acid derivatives were synthesized and tested for their antagonistic activity on the contraction of the rat thoracic aortic ring induced by endothelin-1. Preliminary screening results showed that 6e and 6g with benzoheterocycles demonstrated significant antagonistic activities when compared to the reference compound BQ123. The results from additional assays for the binding affinity and selectivity for endothelin receptors showed that 6e was a selective ETA antagonist with a nanomolar IC50. Moreover, 6e was effective in relieving hypoxia-induced pulmonary arterial hypertension and right ventricular weight ratio. Therefore, 6e may have potential for further development as a therapeutic agent for the treatment of cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)657-667
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number4
DOIs
StatePublished - Feb 15 2015

Bibliographical note

Funding Information:
This work is supported by the Fundamental Research Funds for the Central Universities ( 2242014R30019 ), Technology Supporting Program of Jiangsu Province (BE2012657) and National Basic Research Program of China (No. 2011CB933503).

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

  • Endothelin
  • PAH
  • Phenoxybutanoic acid
  • SAR
  • Synthesis

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