Abstract
Biaryl anthranilides are reported as potent and selective full agonists for the high affinity niacin receptor GPR109A. The SAR presented outlines approaches to reduce serum shift and both CYPCYP2C8 and CYP2C9 liabilities, while improving PK and maintaining excellent receptor activity. Compound 2i exhibited good in vivo antilipolytic efficacy while providing a significantly improved therapeutic index over vasodilation (flushing) with respect to niacin in the mouse model.
MeSH terms
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Amides / chemical synthesis
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Amides / pharmacokinetics
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Amides / pharmacology
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Animals
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
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Binding, Competitive
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CHO Cells
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Cricetinae
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Cricetulus
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Cytochrome P-450 CYP2C8
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Cytochrome P-450 CYP2C9
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Humans
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In Vitro Techniques
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Mice
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Microsomes, Liver / metabolism
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Radioligand Assay
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Receptors, G-Protein-Coupled / agonists*
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Receptors, Nicotinic
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Structure-Activity Relationship
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / pharmacokinetics
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ortho-Aminobenzoates / pharmacology
Substances
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Amides
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HCAR2 protein, human
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HCAR3 protein, human
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Receptors, G-Protein-Coupled
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Receptors, Nicotinic
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ortho-Aminobenzoates
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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