Abstract
The synthesis of seventeen new 1,3-diaryl-5-oxo-proline derivatives as endothelin receptor (ETR) ligands is described. The structural configuration of the new molecules was determined by analyzing selected signals in proton NMR spectra. In vitro binding assays of the human ETA and ETB receptors allowed us to identify compound 31h as a selective ETAR ligand. The molecular docking of the selected compounds and the ETA antagonist atrasentan in the ETAR homology model provided insight into the structural elements required for the affinity and the selectivity of the ETAR subtype.
Highlights
Endothelins (ETs) are a group of peptides involved in vascular homeostasis [1]
Within the the framework framework of of our our studies studies on on endothelin receptor (ETR)
Melting points were determined in a Gallenkamp apparatus (London, UK) with a digital thermometer MFB-595 in glass capillary tubes and were uncorrected
Summary
Endothelins (ETs) are a group of peptides involved in vascular homeostasis [1]. Three different isoforms have been identified and are named endothelin-1, -2, and -3 (ET-1, ET-2, and ET-3) [1]. ET-1 and ET-2 possess higher affinities towards ETA R compared to ET-3 [4], while all three ET isoforms are effective for ETB R [5] Both the ETRs are distributed in several tissues, including vascular smooth muscle and endothelial cells. High plasma concentrations in ETs have been observed in certain pathological conditions where excessive vasoconstriction or smooth muscle proliferation occurs (e.g., systemic hypertension, atherosclerosis, and pulmonary hypertension). These discoveries have aroused great interest among academics and in the pharmaceutical industry, leading to the development of a large number of ETR ligands, especially ETA antagonists, which are useful as antihypertensive drugs
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