Triazole Ligands Reveal Distinct Molecular Features That Induce Histamine H4 Receptor Affinity and Subtly Govern H4/H3 Subtype Selectivity

The histamine H-3 (H3R) and H-4 (H4R) 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 < 10 nM H4R affinities and > 10-fold H4R/H3R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H4R 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.