Abstract
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
MeSH terms
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Administration, Oral
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Anabolic Agents / chemical synthesis*
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Anabolic Agents / pharmacokinetics
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Anabolic Agents / pharmacology
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Androgen Receptor Antagonists*
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Androgens*
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Animals
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Biological Availability
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Bone Density Conservation Agents / chemical synthesis*
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Bone Density Conservation Agents / pharmacokinetics
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Bone Density Conservation Agents / pharmacology
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Female
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Humans
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Hypogonadism / drug therapy
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Hypogonadism / pathology
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Male
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Organ Size / drug effects
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Osteoporosis, Postmenopausal / drug therapy
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Prostate / drug effects
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / pharmacokinetics
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Quinolines / pharmacology
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Quinolones / chemical synthesis*
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Quinolones / pharmacokinetics
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Quinolones / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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6-(2-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-4-trifluoromethylquinolin-2(1H)-one
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Anabolic Agents
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Androgen Receptor Antagonists
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Androgens
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Bone Density Conservation Agents
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Pyrrolidines
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Quinolines
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Quinolones