Abstract
Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
MeSH terms
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Buspirone / pharmacology
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Combinatorial Chemistry Techniques
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Drug Design
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Humans
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
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Molecular Structure
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Receptor, Serotonin, 5-HT1A / drug effects*
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Serotonin Receptor Agonists / chemical synthesis*
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology*
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Structure-Activity Relationship
Substances
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4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine
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4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine
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Indoles
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Pyrimidines
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Serotonin Receptor Agonists
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Receptor, Serotonin, 5-HT1A
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Buspirone