Abstract
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
MeSH terms
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Animals
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Area Under Curve
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Binding, Competitive
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CHO Cells
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacokinetics
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Carboxylic Acids / pharmacology*
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Cricetinae
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Cricetulus
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Cyclohexanecarboxylic Acids / chemistry
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Cyclohexanecarboxylic Acids / pharmacokinetics
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Cyclohexanecarboxylic Acids / pharmacology*
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Cyclohexenes / chemistry*
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Dogs
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Drug Discovery*
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Drug Evaluation, Preclinical
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Fatty Acids, Nonesterified / blood
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Humans
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Metabolic Clearance Rate
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Chemical
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Molecular Structure
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacokinetics
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Oxadiazoles / pharmacology*
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Rats
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Nicotinic / genetics
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Receptors, Nicotinic / metabolism
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Structure-Activity Relationship
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Vasodilation / drug effects
Substances
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Carboxylic Acids
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Cyclohexanecarboxylic Acids
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Cyclohexenes
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Fatty Acids, Nonesterified
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HCAR2 protein, human
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MK 6892
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Oxadiazoles
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Receptors, G-Protein-Coupled
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Receptors, Nicotinic
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cyclohexene