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N-(Heteroaryl)thiop...
N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
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- Wannberg, Johan (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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- Gising, Johan, 1981- (author)
- Uppsala universitet,Preparativ läkemedelskemi,Läkemedelsdesign och läkemedelsutveckling,Science for Life Laboratory, SciLifeLab
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- Henriksson, Martin (author)
- Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
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- Vo, Duc Duy (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för läkemedelskemi
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- Savmarker, Jonas (author)
- Uppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Sallander, Jessica (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
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- Gutiérrez-de-Terán, Hugo (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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- Larsson, Johanna (author)
- Uppsala universitet,Preparativ läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Hamid, Selin (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia.;Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia.
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- Ablahad, Hanin (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia.;Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia.
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- Spizzo, Iresha (author)
- Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia.;Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia.
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- Gaspari, Tracey A. (author)
- Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia.;Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia.
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- Widdop, Robert E. (author)
- Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia.;Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia.
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- Grönbladh, Alfhild, 1983- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Petersen, Nadia N. (author)
- Uppsala universitet,Institutionen för läkemedelskemi,Science for Life Laboratory, SciLifeLab
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- Backlund, Maria (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Hallberg, Mathias, 1971- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Larhed, Mats (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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(creator_code:org_t)
- Elsevier, 2024
- 2024
- English.
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 265
- Related links:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tertbutylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT(2)R selective ligand with a Ki 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 Ki 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(1/2) 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(1/2) = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Angiotensin II type 2 receptor
- AT2R ligands
- N-heteroaryl sulfonamides
- Carboxylic acid bioisosteres
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Wannberg, Johan
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Gising, Johan, 1 ...
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Henriksson, Mart ...
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Vo, Duc Duy
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Savmarker, Jonas
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Sallander, Jessi ...
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show more...
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Gutiérrez-de-Ter ...
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Larsson, Johanna
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Hamid, Selin
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Ablahad, Hanin
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Spizzo, Iresha
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Gaspari, Tracey ...
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Widdop, Robert E ...
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Grönbladh, Alfhi ...
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Petersen, Nadia ...
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Backlund, Maria
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Hallberg, Mathia ...
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Larhed, Mats
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- Articles in the publication
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European Journal ...
- By the university
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Uppsala University