Design, Synthesis, and Structure−Activity Relationships of Acetylene-Based Histamine H3 Receptor Antagonists

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Abstract
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 (Ki = 0.33 ± 0.13 nM) demonstrated a stereopreference in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki = 0.18 ± 0.04 nM) versus the (1S,2S) enantiomer 33 (Ki = 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.