Screening And Pharmacological Evaluation Of ET-1 Receptor Antagonists On Pulmonary Hypertension

Pulmonary hypertension is a kind of disease that occurred most frequently. It can be the primary affection or secondary to other pulmonary or heart disease. There are not many effective drugs for the treatment of pulmonary hypertension, and the mortality of this kind of disease is very high. Till now, ET-1 receptor antagonist is the most promising drug that can be used for pulmonary hypertension. Series of compounds, including ETP508, which were considered to be the antagonists of ET-1 receptor, were synthesized by Beijing Institute of Pharmacology and Toxicology. In this study, the biological activity of these compounds was screened in vitro and in vivo. In addition, hypotensive effect of some active compounds was investigated on hypoxia- and monocrotaline-induced pulmonary hypertension and the structure-efficacy relationship of these compounds was analyzed.1. Screening and structure-efficacy relationship analysis of ET-1 receptor antagonists1.1 In rat thoracic aorta ring experiment in vitro, 24 of 242 compounds inhibited the contraction of aorta ring, IC50 was at nM level, which was similar to positive control BQ-485(IC50=3.4 nM).1.2 ET-1 induced increase in systemic artery pressure (SAP) in anesthetized rat. 12 of the 24 compounds significantly inhibited the increase in SAP induced by ET-1. The inhibitory effect of 6 compounds was better than positive drug BQ-485 (I%=53).1.3 In radio-ligand binding assay, the compounds of which the N-terminal is ABO or HIM significantly inhibited the binding of [125I]-Endothelin-l to ETA-receptor.2. Pharmacological evaluation2.1 In monocrotaline-induced rat pulmonary hypertension, ETP508 , BQ-485 (9.6 mg/day, intravenous infusion) prevented MCT-induced pulmonary hypertension, the inhibition rate of which were 80% and 70%, respectively.2.2 Effect of compounds in chronic hypoxia-induced pulmonary hypertension in rat2 2.1 Peptide compounds ETP020, ETP508 and BQ-485 prevented hypoxia-induced rat pulmonary hypertension with no influence on SAP and heart rate, the inhibition rate of which were 48.6%. 47.4% and 42.9%, respectively. 2.2.2 ETP020 , ETP508 alleviated right ventricular hypertrophy in chronic...