Abstract
The discovery of a novel series of 5-HT(2C) agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT(2A) and 5-HT(2B) receptors were identified. One of the analogues (7 g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Aza Compounds / chemistry
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Azepines / chemistry*
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Azepines / pharmacokinetics
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Azepines / therapeutic use
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Ether-A-Go-Go Potassium Channels / metabolism
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Heterocyclic Compounds, 3-Ring / chemistry*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / therapeutic use
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Humans
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Indenes / chemistry*
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Indenes / pharmacokinetics
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Indenes / therapeutic use
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Male
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Metabolic Diseases / drug therapy*
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Pyrimidines / chemistry
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Rats
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Rats, Wistar
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Receptor, Serotonin, 5-HT2A / chemistry
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Receptor, Serotonin, 5-HT2A / metabolism
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Receptor, Serotonin, 5-HT2B / chemistry
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Receptor, Serotonin, 5-HT2B / metabolism
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Receptor, Serotonin, 5-HT2C / chemistry*
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Receptor, Serotonin, 5-HT2C / metabolism
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Serotonin 5-HT2 Receptor Agonists / chemistry*
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Serotonin 5-HT2 Receptor Agonists / pharmacokinetics
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Serotonin 5-HT2 Receptor Agonists / therapeutic use
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Structure-Activity Relationship
Substances
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Aza Compounds
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Azepines
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Heterocyclic Compounds, 3-Ring
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Indenes
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KCNH2 protein, human
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Pyrimidines
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Receptor, Serotonin, 5-HT2A
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Receptor, Serotonin, 5-HT2B
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Receptor, Serotonin, 5-HT2C
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Serotonin 5-HT2 Receptor Agonists
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pyrimidine