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

作者：Cai Jin; Liu Ligang; Hong Kwon Ho; Wang Peng; Li Lushen; Cao Meng; Sun Chunlong; Wu Xiaoqing; Zong Xi; Chen Junqing; Ji Min^*

来源：Bioorganic & Medicinal Chemistry, 2015, 23(4): 657-667.

DOI：10.1016/j.bmc.2015.01.003

• Endothelin
• Phenoxybutanoic acid
• PAH
• SAR
• Synthesis

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.

• 出版日期2015-2-15
• 单位东南大学