Abstract
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases / drug effects
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Cyclohexenes / chemical synthesis*
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Cyclohexenes / chemistry
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Cyclohexenes / pharmacokinetics
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Cyclohexenes / pharmacology*
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacokinetics
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Cyclopentanes / pharmacology*
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Cytochrome P-450 CYP2C8
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 Enzyme System / metabolism*
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Drug Design
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Humans
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Mice
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Nicotinic Agonists / chemical synthesis*
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Nicotinic Agonists / chemistry
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Nicotinic Agonists / pharmacology*
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Nicotinic Antagonists / pharmacology
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacokinetics
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ortho-Aminobenzoates / pharmacology*
Substances
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Cyclohexenes
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Cyclopentanes
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Nicotinic Agonists
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Nicotinic Antagonists
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ortho-Aminobenzoates
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anthranilic acid
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Cytochrome P-450 Enzyme System
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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CYP2C8 protein, human
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Cytochrome P-450 CYP2C8