Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl-hydroxybicyclohydantoin scaffold.
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.
Sun
Chongqing
C
Bristol-Myers Squibb Pharmaceutical Research Institute, Post Office Box 5400, Princeton, NJ 08543-5400, USA. chongqing.sun@bms.com
Robl
Jeffrey A
JA
Wang
Tammy C
TC
Huang
Yanting
Y
Kuhns
Joyce E
JE
Lupisella
John A
JA
Beehler
Blake C
BC
Golla
Rajasree
R
Sleph
Paul G
PG
Seethala
Ramakrishna
R
Fura
Aberra
A
Krystek
Stanley R
SR
An
Yongmi
Y
Malley
Mary F
MF
Sack
John S
JS
Salvati
Mark E
ME
Grover
Gary J
GJ
Ostrowski
Jacek
J
Hamann
Lawrence G
LG
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
D001952:Bridged-Ring Compounds; D006827:Hydantoins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D008156:Luciferases