Abstract
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP-Binding Cassette Transporters / genetics
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Animals
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Cholesterol 7-alpha-Hydroxylase / genetics
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Drug Stability
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / metabolism
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Imidazoles / pharmacology*
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Male
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Membrane Transport Proteins / genetics
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Molecular Docking Simulation
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PPAR alpha / genetics
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / metabolism
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Pyridines / pharmacology*
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Rats, Sprague-Dawley
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Sterol Regulatory Element Binding Protein 1 / genetics
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Structure-Activity Relationship
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Zolpidem
Substances
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6-chloro-2-(4-chloropyridin-2-yl)-N-(4-methoxybenzyl)imidazo(1,2-a)pyridin-3-amine
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ABCB11 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP-Binding Cassette Transporters
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Imidazoles
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Membrane Transport Proteins
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PPAR alpha
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Pyridines
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Receptors, Cytoplasmic and Nuclear
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Sterol Regulatory Element Binding Protein 1
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nuclear receptor subfamily 0, group B, member 2
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organic solute transporter alpha, human
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farnesoid X-activated receptor
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Zolpidem
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CYP7A1 protein, human
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Cholesterol 7-alpha-Hydroxylase