Key result
Novel thiophene sulfonamides yield AT2R selective ligands with ~5 nM affinity that drive vasorelaxation.
Novel N-(heteroaryl)thiophene sulfonamides were identified as high-affinity AT2R ligands capable of inducing vasorelaxation in preclinical models.
These AT2R ligands merit further preclinical testing; leaves open any role in human cardiovascular therapy.
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 AT2R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT2R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT2R 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 t½ of less than 10 min in human liver microsomes. The most promising ligand, with an AT2R Ki value of 4.9 nM and with intermediate stability in human hepatocytes (t½ = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
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Wannberg et al. (2024) studied Angiotensin AT2 receptor ligands. N-(Heteroaryl)thiophene sulfonamides was evaluated on AT2R binding affinity (Ki) and metabolic stability. Synthesis of N-(heteroaryl)thiophene sulfonamides yielded six AT2R selective ligands with Ki <5 nM, with the most promising ligand (Ki 4.9 nM) causing concentration-dependent vasorelaxation.
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