209599-09-7Relevant 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
supporting information; experimental part, 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.
Design, synthesis, and structure-activity relationships of acetylene- based histamine H3 receptor antagonists
Ali, Syed M.,Tedford, Clark E.,Gregory, Rosilyn,Handley, Michael K.,Yates, Stephen L.,Hirth, Walter W.,Phillips, James G.
, p. 903 - 909 (2007/10/03)
New, potent, and selective histamine H3 receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(±)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S,2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (K(i) = 0.33 ± 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (K(i) = 0.18 ± 0.04 nM) versus the (1S,2S) enantiomer 33 (K(i) = 5.3 ± 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)-imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.
New acetylene based histamine H3 receptor antagonists derived from the marine natural product verongamine
Ali, Syed M.,Tedford, Clark E.,Gregory, Rosilyn,Yates, Stephen L.,Phillips, James G.
, p. 1133 - 1138 (2007/10/03)
New histamine H3 receptor antagonists were developed using an acetylene moiety as a replacement for the amide-oxime functionality of verongamine 5. Optimization of receptor binding was performed by following aliphatic Topliss tree guidelines. These new H3 ligands demonstrate excellent blood-brain barrier penetration.
