lgd-2226 and Hypogonadism

A series of selective androgen receptor modulators (SARMs) with a wide spectrum of receptor modulating activities was developed based on optimization of the 4-substituted 6-bisalkylamino-2-quinolinones (3). Significance of the trifluoromethyl group on the side chains and its interactions with amino acid residues within the androgen receptor (AR) ligand binding domain are discussed. A representative analog (9) was tested orally in a rodent model of hypogonadism and demonstrated desirable tissue selectivity.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Animals; Binding, Competitive; Dihydrotestosterone; Genitalia, Male; Hypogonadism; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Molecular Conformation; Orchiectomy; Organ Size; Organ Specificity; Prostate; Quinolines; Rats; Receptors, Androgen; Structure-Activity Relationship; Transfection

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.

Topics: Administration, Oral; Anabolic Agents; Androgen Receptor Antagonists; Androgens; Animals; Biological Availability; Bone Density Conservation Agents; Female; Humans; Hypogonadism; Male; Muscle, Skeletal; Organ Size; Osteoporosis, Postmenopausal; Prostate; Pyrrolidines; Quinolines; Quinolones; Rats; Stereoisomerism; Structure-Activity Relationship