Abstract
A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.
MeSH terms
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Anabolic Agents / chemical synthesis
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Anabolic Agents / chemistry
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Anabolic Agents / pharmacology
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Androgen Receptor Antagonists / chemical synthesis
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Androgen Receptor Antagonists / chemistry
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Androgen Receptor Antagonists / pharmacology
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Androgens / chemical synthesis*
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Androgens / chemistry
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Androgens / pharmacology
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Animals
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Binding, Competitive
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Bone and Bones / drug effects
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Bone and Bones / physiology
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Crystallography, X-Ray
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Drug Partial Agonism
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HeLa Cells
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Humans
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Hydantoins / chemical synthesis*
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Hydantoins / chemistry
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Hydantoins / pharmacology
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Male
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Models, Molecular
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Orchiectomy
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Prostate / drug effects
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Prostate / physiology
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Rats
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Transcriptional Activation / drug effects
Substances
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4-(3,4-dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile
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Anabolic Agents
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Androgen Receptor Antagonists
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Androgens
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Hydantoins
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Receptors, Androgen