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

被引:1
|
作者
Wannberg, Johan [1 ]
Gising, Johan [2 ]
Henriksson, Martin [3 ]
Vo, Duc Duy [1 ]
Savmarker, Jonas [2 ]
Sallander, Jessica [4 ]
Gutierrez-de-Teran, Hugo [4 ]
Larsson, Johanna [1 ]
Hamid, Selin [5 ,6 ,7 ]
Ablahad, Hanin [5 ,6 ,7 ]
Spizzo, Iresha [6 ,7 ]
Gaspari, Tracey A. [6 ,7 ]
Widdop, Robert E. [6 ,7 ]
Gronbladh, Alfhild [5 ]
Petersen, Nadia N. [2 ]
Backlund, Maria [8 ,9 ]
Hallberg, Mathias
Larhed, Mats [2 ]
机构
[1] Uppsala Univ, Dept Med Chem, Sci Life Lab, BMC, Box 574, SE-75123 Uppsala, Sweden
[2] Uppsala Univ, Dept Med Chem, Beijer Lab, Sci Life Lab,BMC, Box 574, S-75124 Uppsala, Sweden
[3] Stockholm Univ, Dept Organ Chem, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden
[4] Uppsala Univ, Dept Cell & Mol Biol, BMC, Box 596, SE-75124 Uppsala, Sweden
[5] Uppsala Univ, Dept Pharmaceut Biosci Neuropharmacol & Addict Res, Beijer Lab, BMC, S-75124 Uppsala, Sweden
[6] Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia
[7] Monash Univ, Biomed Discovery Inst, Clayton, Vic 3800, Australia
[8] Uppsala Univ, Dept Pharm, Uppsala, Sweden
[9] Uppsala Univ, Sci Life Lab, Drug Optimizat & Pharmaceut Profiling Platform UDO, Uppsala, Sweden
基金
英国医学研究理事会;
关键词
Angiotensin II type 2 receptor; AT2R ligands; N-heteroaryl sulfonamides; Carboxylic acid bioisosteres; TYPE-2; RECEPTOR; ACCURATE DOCKING; NEUROPATHIC PAIN; AT(2) RECEPTORS; AT(1) RECEPTOR; BLOOD-PRESSURE; BINDING; RENIN; GLIDE; PHARMACOLOGY;
D O I
10.1016/j.ejmech.2024.116122
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页数:11
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