Abstract
4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.
MeSH terms
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Administration, Oral
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Animals
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Benzoates / chemical synthesis*
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Benzoates / chemistry
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Benzoates / pharmacology
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Binding Sites
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Biological Availability
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology
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Cells, Cultured
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Humans
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Models, Molecular
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Protein Isoforms / agonists
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Protein Structure, Tertiary
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Rats
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Receptors, Retinoic Acid / agonists*
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Solubility
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Transcription, Genetic
Substances
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4'-octyl-4-biphenylcarboxylic acid
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4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid
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Benzoates
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Biphenyl Compounds
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Protein Isoforms
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Receptors, Retinoic Acid
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Thiazoles
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retinoic acid receptor beta