Abstract
A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPgammaS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.
MeSH terms
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Animals
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Attention / drug effects
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Avoidance Learning / drug effects
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Blood Proteins / metabolism
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Blood-Brain Barrier / metabolism
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Calcium / metabolism
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Cell Line
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Cognition / drug effects
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Dogs
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Drug Inverse Agonism
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Drug Stability
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Haplorhini
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Humans
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Protein Binding
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / pharmacokinetics
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Quinolines / pharmacology
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Radioligand Assay
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Rats
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Rats, Inbred SHR
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Receptors, Histamine H3 / metabolism*
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Recognition, Psychology / drug effects
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Social Behavior
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Stereoisomerism
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Structure-Activity Relationship
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Tissue Distribution
Substances
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2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(2-(2-methylpyrrolidin-1-yl)ethyl)quinoline
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2-(2,7-dimethylpyrazolo(1,5-a)pyrimidin-6-yl)-6-(2-(2-methylpyrrolidin-1-yl)ethyl)quinoline
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Blood Proteins
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Pyrazoles
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Pyrimidines
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Quinolines
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Receptors, Histamine H3
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Calcium