Abstract
5-HT(6) receptors are exclusively localized in the CNS and have high affinity with many psychotropic agents. Though the role of this receptor in many CNS diseases is widely anticipated, lack of definite progress in the development of 5-HT(6) receptor-oriented drugs indicates a need for further discoveries of novel chemotypes with high potency and high selectivity to the receptor. Here we present preparations and biological evaluation of a series of (3-phenylsulfonylcycloalkano[e and d]pyrazolo[1,5-a]pyrimidin-2-yl)amines. Phenylsulfonylcyclopentapyrazolopyrimidine 7 was found to be a highly selective 5-HT(6) receptor antagonist with high affinity (low picomolar range) and potency. 7 and a few of its analogues were further tested for biological effect on 5-HT(2B) receptors and hERG potassium channels, potential liability targets. Such liability appears to be minimal, based on the in vitro data.
MeSH terms
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Cell Line
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Crystallography, X-Ray
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Models, Molecular
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Molecular Structure
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Radioligand Assay
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Receptors, Serotonin / metabolism*
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
Substances
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Amines
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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N-methyl-(3-phenylsulfonyl)-7,8-dihydro-6H-cyclopenta(e)pyrazolo(1,5-a)pyrimidin-2-amine
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Pyrazoles
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Pyrimidines
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Receptors, Serotonin
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Serotonin 5-HT2 Receptor Antagonists
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Serotonin Antagonists
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Sulfones
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serotonin 6 receptor