Abstract
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
MeSH terms
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Animals
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Azetidines / chemical synthesis
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Azetidines / pharmacokinetics
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Azetidines / pharmacology
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CHO Cells
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Cell Membrane Permeability
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Cognition / drug effects*
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Cricetinae
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Cricetulus
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Cyclopropanes / chemical synthesis*
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Cyclopropanes / pharmacokinetics
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Cyclopropanes / pharmacology
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Dogs
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Histamine H3 Antagonists / chemical synthesis*
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Histamine H3 Antagonists / pharmacokinetics
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Histamine H3 Antagonists / pharmacology
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Humans
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Learning / drug effects
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Madin Darby Canine Kidney Cells
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Male
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Piperidines / chemical synthesis
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Pyrrolidines / chemical synthesis
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Histamine H3 / genetics
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Receptors, Histamine H3 / metabolism*
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Recognition, Psychology / drug effects
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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(4-isopropylpiperazin-1-yl)(6-(tetrahydro-2H-pyran-4-yl)-6-azaspiro(2.5)octan-1-yl)methanone
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Azetidines
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Cyclopropanes
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Histamine H3 Antagonists
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Piperazines
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Piperidines
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Pyrrolidines
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Receptors, Histamine H3
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Spiro Compounds