Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Li
James J
JJ
Discovery Chemistry, Computer Assisted Drug Design, Metabolic Disease Research, Metabolism and Pharmacokinetics, Discovery Analytical Sciences, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. James.Li@bms.com
Sutton
James C
JC
Nirschl
Alexandra
A
Zou
Yan
Y
Wang
Haixia
H
Sun
Chongqing
C
Pi
Zulan
Z
Johnson
Rebecca
R
Krystek
Stanley R
SR
Seethala
Ramakrishna
R
Golla
Rajasree
R
Sleph
Paul G
PG
Beehler
Blake C
BC
Grover
Gary J
GJ
Fura
Aberra
A
Vyas
Viral P
VP
Li
Cindy Y
CY
Gougoutas
Jack Z
JZ
Galella
Michael A
MA
Zahler
Robert
R
Ostrowski
Jacek
J
Hamann
Lawrence G
LG
D000284:Administration, Oral; D045930:Anabolic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D006207:Half-Life; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects*; D009919:Orchiectomy; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C531039:2-chloro-4-(1-ethyl-7-hydroxy-3-oxotetrahydro-1H-pyrrolo(1,2-e)imidazol-2(3H)-yl)-3-methylbenzonitrile; D045930:Anabolic Agents; D007093:Imidazoles; D011758:Pyrroles; D011944:Receptors, Androgen