A series of novel benzofuran carboxylic acid derivatives have been designed and synthesized, with their antagonism effect screened on ET-1-induced contraction in the rat thoracic aortic ring. Some target compounds demonstrated significant inhibitory activity, especially benzo[c]thiadiazole and benzo[c]oxadiazole compounds 29 and 30 showed potent inhibition percentage higher than the contrast compound BQ123. Further affinity and selectivity for ET binding assay showed that 29 demonstrated a dual ETA/ETB antagonism activity in nanomole level. Moreover, 30 was effective in relieving hypoxia-induced pulmonary arterial hypertension.