The Study Of Endothelin Receptor Antagonists

Endothelin(ET) is a potent vasoconstrictive peptide which contains 21 amino acid residues. It has a molecular weight of 2492, free carboxyl and amino termini and has two intramolecular disulfide bonds. Because ET and its receptors exist in human body widely and play major biological parts, ET has been implicated as a pathogenic factor for a variety of diseases, including hypertension, pulmonary arterial hypertension, heart failure, renal failure, atherosclerosis and cerebral vasospasm, and so on. Now, the study on endothelin receptor antagonist has been one of the hotspots in this field. Bosentan is the first drug of this kind of antagonists and has been used for treatment of pulmonary arterial hypertension.Referring to plenty of informations on ET receptor antagonists, we selected two ETA antagonists, BQ-123 and BQ-485, as lead compounds to develop new derivatives. They have the characters of strong ET antagonistic potency, and BQ-123 was in clinical trials.Based on the structure-activity studies of the leading compounds, we designed and synthesized a new series of ET receptor antagonists with different N-terminal chemical groups and unnatural amino acids. Through the ET receptor antagonistic activities were screened, we selected some tripeptides as leading compounds, designed and synthesized a novel series of pseudo-peptides as ET receptor antagonists.In this thesis, we reported the synthesis and resolution of 4 unnatrual amino acids. 192 new tripeptides were synthesized, 53 of them showed inhibiting activity to endothelin receptor in vitro and 18 of them were more active than BQ-485. 9 new pseudo-peptides were synthesized and their antagonistic activities were in the same level of BQ-485. Through the measurement of blood pressure in rats induced by ET-1, all the 25 tripeptides could reduce the pressure effectively, and 12 of them were more active than the control, BQ-485, or at the same level.The primary structure-activity relationships of these compounds were concluded roughly according to the current data. 1) N-terminal chemical group showed crucial function in improving its selectivity and affinity to ET receptor. ABO showed high ETAreceptor binding activity than others; 2) The first amino acid AA1 showed high hydrophobic dependence, Leu is the best; 3) Replaced the second amide fragment -CO-NH- with -CO-CH2-, the activity still survived, enzyme degradation of a peptide might be inhibited by this change; 4) The third amino acid AA3 should be D-isomer, L-amino acid did not show inhibiting activity based on our observation.