223419-69-0Relevant academic research and scientific papers
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 (1998)
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.
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.
