title: Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats.
abstract: A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.
authors.affiliation: Department of Metabolic Diseases, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Kuhns
authors.forename: John A
authors.initials: JA
authors.lastname: Lupisella
authors.forename: Mark C
authors.initials: MC
authors.lastname: Manfredi
authors.forename: Blake C
authors.initials: BC
authors.lastname: Beehler
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Bi
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Paul G
authors.initials: PG
authors.lastname: Sleph
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Kish
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Kasim A
authors.initials: KA
authors.lastname: Mookhtiar
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Grover
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D013196:Dihydrotestosterone / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects* / Q000502:physiology; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C516977:BMS-564929; D007093:Imidazoles; D008024:Ligands; D011758:Pyrroles; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D007986:Luteinizing Hormone; D001141:Aromatase