N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands.

Autor: Wannberg J; Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden., Gising J; The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden., Henriksson M; Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden., Vo DD; Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden., Sävmarker J; The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden., Sallander J; Department of Cell and Molecular Biology, BMC, Box 596, Uppsala University, SE-751 24, Uppsala, Sweden., Gutiérrez-de-Terán H; Department of Cell and Molecular Biology, BMC, Box 596, Uppsala University, SE-751 24, Uppsala, Sweden., Larsson J; Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden., Hamid S; The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden; Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia., Ablahad H; The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden; Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia., Spizzo I; Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia., Gaspari TA; Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia., Widdop RE; Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia., Grönbladh A; The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden., Petersen NN; The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden., Backlund M; Department of Pharmacy, Uppsala University, Uppsala, Sweden and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory, Uppsala, Sweden., Hallberg M; The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden., Larhed M; The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden. Electronic address: mats.larhed@ilk.uu.se.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 05; Vol. 265, pp. 116122. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1016/j.ejmech.2024.116122
Abstrakt: Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tert-butylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT 2 R selective ligand with a K i of 42 nM was identified in the first series and in the second series, six AT 2 R selective ligands with significantly improved binding affinities and K i values of <5 nM were discovered. The binding modes to AT 2 R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t ½ of less than 10 min in human liver microsomes. The most promising ligand, with an AT 2 R K i value of 4.9 nM and with intermediate stability in human hepatocytes (t ½  = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Crown Copyright © 2024. Published by Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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