title: Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold.
abstract: A novel, N-aryl-bicyclohydantoin selective androgen receptor modulator scaffold was discovered through structure-guided modifications of androgen receptor antagonists. A prototype compound (7R,7aS)-10b from this series is a potent and highly tissue-selective agonist of the androgen receptor. After oral dosing in a rat atrophied levator ani muscle model, (7R,7aS)-10b demonstrated efficacy at restoring levator ani muscle mass to that of intact controls and exhibited >50-fold selectivity for muscle over prostate.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 5400, Princeton, NJ 08543-5400, USA. chongqing.sun@bms.com
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Yanting
authors.initials: Y
authors.lastname: Huang
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Kuhns
authors.forename: John A
authors.initials: JA
authors.lastname: Lupisella
authors.forename: Blake C
authors.initials: BC
authors.lastname: Beehler
authors.forename: Rajasree
authors.initials: R
authors.lastname: Golla
authors.forename: Paul G
authors.initials: PG
authors.lastname: Sleph
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Mary F
authors.initials: MF
authors.lastname: Malley
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: Mark E
authors.initials: ME
authors.lastname: Salvati
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Grover
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000254:growth & development; D009133:Muscular Atrophy / Q000188:drug therapy*; D032446:Myoblasts / Q000187:drug effects; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D001952:Bridged-Ring Compounds; D006827:Hydantoins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D008156:Luciferases