Design And Synthesis Of Endothelin Receptor Antagonist

Endothelin(ET) is a family of peptides containing 21 amino acids with potent vasoconstrictor properties that was originally identified in conditioned medium from cultured porcine endothelial cells. Endothelin has been implicated in the pathophysiology of a large number of diseases. To overcome the unwanted effects of an abnormally regulated ET system, ET receptor antagonists are used in the treatment of these diseases.Referring to plenty of informations on ET receptor antagonists and previous studies, we selected ETA antagonist ABT-627 as leading compound to develop new derivatives. By designing rigid nucleus, changing the ureido-structure of N terminal, and introducing some unnatural amino acids as well as non-amino groups, we could change characters such as molecular conformation definition, hydrophilic property, and so on. Through the ET receptor antagonistic activities were screened, we do our best to find one kind of peptide mimics ET receptor antagonists maintaining the high activity, increasing aqueous solubility, further lightening the skin irritation brought by the intramuscular injection, reducing the liver poisonous side effect, and antagonizing enzymolysis.In this study,19 new compounds have been designed and synthesized, then purified by the middle pressure liquid chromatography (MPLC). The purity was analyzed by the HPLC. The structures of compounds have been determined by the mass spectrum (MS), the nuclear magnetic resonance (1H NMR).Comparing to the reported ET antagonist Bosentan, the results of preliminary screening tests in vitro showed that 4 compounds had similar activities. The primary structure-activity relationships of these compounds were deduced roughly according to the current data:1) peptide mimics ET receptor antagonists can bind with the receptor effectively, and inhibit vasoconstriction induced by ET-1; 2) the ureido-structure at the N terminus could be not an indispensable group; 3) when the substituent of D-Phe is fluorine, chlorine, or carboxyl, the compounds could have higher activity; 4) containing indole ring non-amino acid unit such as (1H-indol-3-yl) acetyl could simulate the feature of D-Trp residue.5) the conformation freedom of free carboxyl may affect the activity.