We present a novel series of Selective Androgen Receptor Modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitriles (1 ) show potent binding to the androgen receptor (AR) and activate AR-mediated transcription in vitro. Representative compounds demonstrate diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C termini interaction is useful as a biomarker to decouple undesired androgenic response from anabolic activity. In castrated rats, the daily administration of a lead compound shows anabolic activity by increasing levator ani muscle weight. Minimal effects were observed on the prostate, and seminal vesicles along with minimal effects repressing circulating luteinizing hormone (LH) levels. A lead compound completed a two week rat toxicology study, and it was well tolerated at dosages up to 100 mg/kg/day for 14 consecutive days, the highest dosage evaluated.                                                                        

Novel class of selective androgen receptor modulators (SARMs) for the treatment of muscle frailty

246th National Meeting (2013)

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