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  • In conclusion a series of endothelin

    2020-08-05

    In conclusion, a series of endothelin receptor antagonists was synthesized and evaluated for their ET and ET receptor antagonist activity and selectivity using GeneBLAzer® FRET assay technology. The structure activity relationship deduced for the carboxylic PD 151746 series was found to parallel that of the tetrazole series. The -propoxy analogue in the tetrazole series was found to be the most potent and selective ET receptor antagonist with an IC value of 0.8nM and an ET-selectivity of 1004. Target compounds with ethoxy, -propoxy, -butoxy, -butoxy substituents in both series were found to have similar or better activity than the positive control BQ-123. These results suggest that short chain saturated alkoxy groups at position 6 of the 4-oxo-1,4-dihydro-quinoline-2-carboxylic acid impart good ET receptor antagonism and selectivity over ET receptor. Tetrazole exhibits similar or better ET receptor antagonist activity as compared to the clinically approved endothelin receptor antagonists for PAH () with ET-selectivity profile similar to that of the most recently approved drug, macitentan. Acknowledgments The authors thank Dr. Vladimir Poltoratsky and Zhihui Xiao for their help with the in vitro FRET assay. Support for this research was provided by Saint John’s University.
    Introduction We predicted the existence of endothelium-derived contractile factors (EDCFs) in 1982 [1]. In 1988, one of these EDCFs was identified as the 21-amino-acid bicyclic peptide endothelin-1 (ET1), which causes sustained and long-lasting vasoconstrictor and vasopressor effects [2]. The endothelin system in mammals includes three 21-amino-acid bicyclic signaling peptides (ET1, ET2 and ET3), the enzymes involved in their synthesis and degradation (endothelin-converting enzymes and, to a lesser extent, chymase and neutral endopetidase) and two G protein-coupled receptors (GPCRs, ETA and ETB) 3, 4, 5. These GPCRs are involved in embryonic development and cardiovascular homeostasis, and in the pathogenesis of cardiovascular and renal diseases, diabetes, cancers and chronic pain 6, 7, 8, 9, 10. Prolonged ETA stimulation causes vasospasm, inflammation, oxidative stress, and cell growth and proliferation. In blood vessels, endothelial ETBs counteract these deleterious effects of ETA[11] and scavenge ET1 from the circulation 12, 13. There is ongoing debate on the therapeutic effects of selective ETA versus mixed ETA and ETB antagonists [8]. Here we focus on the peculiar molecular pharmacology of ETA. Based on its amino acid sequence, ETA is a class A GPCR 5, 14. Compared with the well-known rhodopsin, β-adrenoceptor, adenosine and muscarinic members of this family [15], it displays atypical pharmacological properties. Most notably, agonist-induced effects of ETA stimulation persist for several hours and are little affected by desensitization, tachyphylaxis or tolerance 2, 4, 16. In this article, we discuss the mechanisms and consequences of long-lasting ET1-induced ETA-mediated effects.