Abstract
Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.
MeSH terms
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Adipocytes / drug effects
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Adipocytes / metabolism
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Cycloparaffins / adverse effects
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Cycloparaffins / chemical synthesis*
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Cycloparaffins / pharmacology
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Ear / blood supply
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Flushing / chemically induced*
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Heterocyclic Compounds, 3-Ring / adverse effects
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Hypolipidemic Agents / adverse effects
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Hypolipidemic Agents / chemical synthesis*
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Hypolipidemic Agents / pharmacology
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In Vitro Techniques
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Lipolysis
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Male
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Mice
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Niacin / metabolism*
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Radioligand Assay
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Rats
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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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Vasodilation / drug effects
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ortho-Aminobenzoates / adverse effects
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / pharmacology
Substances
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Cycloparaffins
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HCAR2 protein, human
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HCAR3 protein, human
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Heterocyclic Compounds, 3-Ring
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Hypolipidemic Agents
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Receptors, G-Protein-Coupled
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Receptors, Nicotinic
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ortho-Aminobenzoates
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Niacin