406225-22-7Relevant academic research and scientific papers
Triazole ligands reveal distinct molecular features that induce histaine H4 receptor affinity and subtly govern H4/H3 subtype selectivity
Wijtmans, Maikel,De Graaf, Chris,De Kloe, Gerdien,Istyastono, Enade P.,Smit, Judith,Lim, Herman,Boonnak, Ratchanok,Nijmeijer, Saskia,Smits, Rogier A.,Jongejan, Aldo,Zuiderveld, Obbe,De Esch, Iwan J. P.,Leurs, Rob
, p. 1693 - 1703 (2011/05/05)
The histamine H3 (H3R) and H4 (H 4R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H4R/H3R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with 4R affinities and >10-fold H 4R/H3R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H 4R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H3R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H4R over H3R selectivity.
New high affinity H3 receptor agonists without a basic side chain
Kitbunnadaj, Ruengwit,Hoffmann, Marcel,Fratantoni, Silvina A.,Bongers, Gerold,Bakker, Remko A.,Wieland, Kerstin,El Jilali, Ahmed,De Esch, Iwan J. P.,Menge, Wiro M. P. B.,Timmerman, Henk,Leurs, Rob
, p. 6309 - 6323 (2007/10/03)
In this study, we replaced the basic amine function of the known histamine H3 receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H3 receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H3 receptor over the human H4 receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H3 receptor agonist (pKi = 8.0 and pEC50 = 8.1) with a 320-fold selectivity at the human H3 receptor over the human H 4 receptor.
ω-(Imidazol-4-yl)alkane-1-sulfonamides: a new series of potent histamine H3 receptor antagonists
Tozer, Matthew J.,Buck, Ildiko M.,Cooke, Tracey,Kalindjian,Pether, Michael J.,Steel, Katherine I.M.
, p. 425 - 432 (2007/10/03)
ω-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H3 receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and vinylsulfonamide analogues. This complements and completes the existing set of imidazole-based sulfonamides and sulfamides. Copyright
