title: Discovery of phenoxybutanoic acid derivatives as potent endothelin antagonists with antihypertensive activity.
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.
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
authors.forename: Kwon Ho
authors.initials: KH
authors.lastname: Hong
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Lushen
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Cao
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zong
authors.affiliation: School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D065128:Endothelin Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D002087:Butyrates; D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin
keywords: Endothelin; PAH; Phenoxybutanoic acid; SAR; Synthesis