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 ET A antagonist with a nanomolar IC 50 . 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.