2. Academic Validation
  3. N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands

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

  • Eur J Med Chem. 2024 Feb 5:265:116122. doi: 10.1016/j.ejmech.2024.116122.
Johan Wannberg 1,  Johan Gising 2,  Martin Henriksson 3,  Duc Duy Vo 1,  Jonas Sävmarker 2,  Jessica Sallander 4,  Hugo Gutiérrez-de-Terán 4,  Johanna Larsson 1,  Selin Hamid 5,  Hanin Ablahad 5,  Iresha Spizzo 6,  Tracey A Gaspari 6,  Robert E Widdop 6,  Alfhild Grönbladh 7,  Nadia N Petersen 2,  Maria Backlund 8,  Mathias Hallberg 7,  Mats Larhed 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden.
  • 2 The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
  • 3 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
  • 4 Department of Cell and Molecular Biology, BMC, Box 596, Uppsala University, SE-751 24, Uppsala, Sweden.
  • 5 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.
  • 6 Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia.
  • 7 The Beijer Laboratory, Department of Pharmaceutical Biosciences, Neuropharmacology and Addiction Research, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
  • 8 Department of Pharmacy, Uppsala University, Uppsala, Sweden and Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory, Uppsala, Sweden.
  • 9 The Beijer Laboratory, Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Box 591, 751 24, Uppsala, Sweden. Electronic address: [email protected].
PMID: 38199164 DOI: 10.1016/j.ejmech.2024.116122
Abstract

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.

Keywords

AT(2)R ligands; Angiotensin II type 2 receptor; Carboxylic acid bioisosteres; N-heteroaryl sulfonamides.

Figures
Products