| Abstract
| - A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgenreceptor (AR). These ligands were designed to eliminate metabolic sites identified in one ofour first-generation AR agonists, which was inactive in vivo due to its rapid metabolism toinactive constituents. The binding affinity of these compounds was evaluated using AR isolatedfrom rat ventral prostate. These second-generation compounds bound the AR in a high affinityand stereoselective manner, with Ki values ranging from about 4 to 130 nM. The ability ofthese ligands to stimulate AR-mediated transcriptional activation was examined in cellstransfected with the human AR and a hormone-dependent luciferase reporter gene. Althoughsome compounds were unable to stimulate AR-mediated transcription, several demonstratedactivity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for theAR). We also evaluated the in vivo pharmacologic activity of selected compounds in castratedmale rats. Three compounds were identified as selective androgen receptor modulators (SARMs),exhibiting significant anabolic activity while having only moderate to minimal androgenicactivity in vivo.
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