Abstract
We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor.
MeSH terms
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Animals
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Binding, Competitive
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CHO Cells
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Combinatorial Chemistry Techniques
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Cricetinae
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Cricetulus
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Drug Design
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Drug Partial Agonism
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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Guinea Pigs
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Humans
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Hypothermia / drug therapy
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Lipidoses / chemically induced
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Lipidoses / metabolism
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Phospholipids / metabolism
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Piperazines / adverse effects
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Piperazines / chemical synthesis
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Piperazines / pharmacology
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Pyrazoles / adverse effects
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology
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Radioligand Assay
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT1 Receptor Antagonists*
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Structure-Activity Relationship
Substances
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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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Phospholipids
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Piperazines
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Pyrazoles
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Serotonin 5-HT1 Receptor Agonists
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Serotonin 5-HT1 Receptor Antagonists