Structure-efficacy Relationship And Pharmacodynamics Of Neotype ET_A Receptor Antagonists On Pulmonary Hypertension

Objective: The aim of the present study is to evaluate the structure-efficacy relationship of new ET_A receptor antagonists which were synthesized by Beijing Institute of Pharmacology and Toxicology at the base of previous compound ETP508, in order to provide evidence for discover new anti-pulmonary hypertensive drugs. Methods: 1. The biological activity and toxicity of compounds was evaluated at first. 2. The structure-efficacy relationship of these compounds was analyzed in vivo and in vitro, 3. The anti-pulmonary hypertensive effect of some active compounds was investigated on hypoxia-induced pulmonary hypertension. Result: 1. The toxicity of new type tripeptide antagonist of ET_A receptor was lower than previous compounds, and the solubility was increased, but there was significant dermat-toxicity in new-synthesized compounds as well as in previous compound-ETP508. 2. Activity screening of ET_A receptor antagonists in radio-ligand binding assay indicated that the binding activity to ET_A-receptor of the compounds was lower than ETP508 and positive control BQ-485. In rat thoracic aorta ring experiment in vitro and ET-1 induced- hypertension experiment in anesthetized rat, 8 compounds were similar to ETP508 and positive control BQ-485. 3. In chronic hypoxia-induced rat pulmonary hypertension models, pretreatment with compound ETP508 can partly prevent pulmonary hypertension, alleviated right ventricular hypertrophy and the remodeling of small pulmonary arteries, but GF004 group can not. Pretreatment with compound GF009 or GF063 for 2 weeks prevented chronic hypoxia-induced pulmonary hypertension in rats, the effect of which was similar to ETP508, but these was no effect on right ventricular hypertrophy. Conclusion: Analysis of structure-efficacy relationship suggested that toxicology of the neotype ET_A receptor antagonists was lowered and solubility was improved by structural modification of adding hydrophilic R group or replacing 2- or 3- amino acid at the base of previous compound ETP508 , but preventive and therapeutic effect of the compounds was lowered on hypoxia-induced pulmonary hypertension in rats. Meanwhile, the new compounds still remained significant dermat-toxicity, which was possibly resulted from adding unnatural amino acid or hydrophilic R group in structure.