Abstract
A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
MeSH terms
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Administration, Oral
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Animals
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Breast Neoplasms / drug therapy
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Bridged-Ring Compounds / chemical synthesis
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Bridged-Ring Compounds / chemistry
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Bridged-Ring Compounds / pharmacology*
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Cells, Cultured
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Dihydrotestosterone / pharmacology
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Humans
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Hydantoins / administration & dosage
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Hydantoins / chemical synthesis
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Hydantoins / chemistry
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Hydantoins / pharmacology*
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Luciferases / metabolism
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Male
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Mice
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Muscle, Skeletal / drug effects*
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Muscle, Skeletal / growth & development
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Muscular Atrophy / drug therapy*
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Myoblasts / drug effects
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Rats
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Receptors, Androgen / metabolism*
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Transcriptional Activation
Substances
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Bridged-Ring Compounds
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Hydantoins
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Receptors, Androgen
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Dihydrotestosterone
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Luciferases