title: Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators.
abstract: A series of nonsteroidal ligands were synthesized as second-generation agonists for the androgen receptor (AR). These ligands were designed to eliminate metabolic sites identified in one of our first-generation AR agonists, which was inactive in vivo due to its rapid metabolism to inactive constituents. The binding affinity of these compounds was evaluated using AR isolated from rat ventral prostate. These second-generation compounds bound the AR in a high affinity and stereoselective manner, with K(i) values ranging from about 4 to 130 nM. The ability of these ligands to stimulate AR-mediated transcriptional activation was examined in cells transfected with the human AR and a hormone-dependent luciferase reporter gene. Although some compounds were unable to stimulate AR-mediated transcription, several demonstrated activity similar to that of dihydrotestosterone (DHT, an endogenous steroidal ligand for the AR). We also evaluated the in vivo pharmacologic activity of selected compounds in castrated male rats. Three compounds were identified as selective androgen receptor modulators (SARMs), exhibiting significant anabolic activity while having only moderate to minimal androgenic activity in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Health Science Center, 847 Monroe Avenue, Johnson Building, Room 227C, The University of Tennessee, Memphis, Tennessee 38163, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Marhefka
authors.forename: Wenqing
authors.initials: W
authors.lastname: Gao
authors.forename: Kiwon
authors.initials: K
authors.lastname: Chung
authors.forename: Juhyun
authors.initials: J
authors.lastname: Kim
authors.forename: Yali
authors.initials: Y
authors.lastname: He
authors.forename: Donghua
authors.initials: D
authors.lastname: Yin
authors.forename: Casey
authors.initials: C
authors.lastname: Bohl
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045930:Anabolic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000728:Androgens; D000818:Animals; D001667:Binding, Competitive; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009919:Orchiectomy; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000737:chemistry; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects* / Q000302:isolation & purification; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D000577:Amides; D045930:Anabolic Agents; D000728:Androgens; D008024:Ligands; D011422:Propionates; D011944:Receptors, Androgen; D008156:Luciferases