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

doi:10.1016/j.bmc.2015.01.003

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

Bioorg Med Chem. 2015 Feb 15;23(4):657-67. doi: 10.1016/j.bmc.2015.01.003. Epub 2015 Jan 8.

Authors

Jin Cai¹, Ligang Liu¹, Kwon Ho Hong², Peng Wang³, Lushen Li³, Meng Cao³, Chunlong Sun¹, Xiaoqing Wu⁴, Xi Zong¹, Junqing Chen¹, Min Ji⁵

Affiliations

¹ School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
² Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
³ School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
⁴ Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
⁵ School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China; School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China. Electronic address: jimin@seu.edu.cn.

PMID: 25614116
DOI: 10.1016/j.bmc.2015.01.003

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.

Keywords: Endothelin; PAH; Phenoxybutanoic acid; SAR; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antihypertensive Agents / chemistry*
Antihypertensive Agents / pharmacology*
Aorta, Thoracic / drug effects
Aorta, Thoracic / physiology
Butyrates / chemistry*
Butyrates / pharmacology*
Drug Discovery
Endothelin Receptor Antagonists / chemistry*
Endothelin Receptor Antagonists / pharmacology*
Models, Molecular
Rats
Rats, Sprague-Dawley
Receptors, Endothelin / metabolism
Structure-Activity Relationship
Vasoconstriction / drug effects*

Substances

Antihypertensive Agents
Butyrates
Endothelin Receptor Antagonists
Receptors, Endothelin