Abstract
Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.
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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Biological Availability
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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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Molecular Conformation
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Muscle, Skeletal / anatomy & histology
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Orchiectomy
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Organ Size / drug effects
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Prostate / anatomy & histology
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Prostate / drug effects
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Prostate / metabolism
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Rats
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Rats, Sprague-Dawley
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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-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-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