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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1999-03, Vol.42 (5), p.903-909
Main Authors: Ali, Syed M, Tedford, Clark E, Gregory, Rosilyn, Handley, Michael K, Yates, Stephen L, Hirth, Walter W, Phillips, James G
Format: Article
Language:English
Subjects:
Acetylene - chemistry
Animals
Biological and medical sciences
Cerebral Cortex - metabolism
Drug Design
Histamine Antagonists - chemical synthesis
Histamine Antagonists - chemistry
Histamine Antagonists - metabolism
Histamine Antagonists - pharmacology
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
In Vitro Techniques
Medical sciences
Miscellaneous
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Rats
Receptors, Histamine H3 - drug effects
Receptors, Histamine H3 - metabolism
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm980310g