title: Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.
abstract: 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.
authors.affiliation: 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
authors.forename: James J
authors.initials: JJ
authors.lastname: Li
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nirschl
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.forename: Chongqing
authors.initials: C
authors.lastname: Sun
authors.forename: Zulan
authors.initials: Z
authors.lastname: Pi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Johnson
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
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: Blake C
authors.initials: BC
authors.lastname: Beehler
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Grover
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Viral P
authors.initials: VP
authors.lastname: Vyas
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Li
authors.forename: Jack Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: Michael A
authors.initials: MA
authors.lastname: Galella
authors.forename: Robert
authors.initials: R
authors.lastname: Zahler
authors.forename: Jacek
authors.initials: J
authors.lastname: Ostrowski
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: 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
chemical_list: 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