Abstract
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
MeSH terms
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Administration, Oral
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Animals
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology*
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Cholestasis / drug therapy*
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Cholestasis / metabolism
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Cholestasis / pathology
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Crystallography, X-Ray
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DNA-Binding Proteins / agonists*
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DNA-Binding Proteins / chemistry
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Disease Models, Animal
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Dogs
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Gastric Mucosa / metabolism
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Haplorhini
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology*
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Mice
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Molecular Conformation
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Molecular Structure
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Rats
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / chemistry
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Stomach / drug effects
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Structure-Activity Relationship
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Transcription Factors / agonists*
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Transcription Factors / chemistry
Substances
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Carboxylic Acids
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DNA-Binding Proteins
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Isoxazoles
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Naphthalenes
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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farnesoid X-activated receptor
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1-naphthoic acid
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GW 4064