title: 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulators.
abstract: We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days.
authors: BioTherapeutics Medicinal Chemistry, Pfizer Global Research and Development , 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, United States.
authors: Eugene L
authors: EL
authors: Piatnitski Chekler
authors: Rayomond
authors: R
authors: Unwalla
authors: Taukeer A
authors: TA
authors: Khan
authors: Raghuram S
authors: RS
authors: Tangirala
authors: Mark
authors: M
authors: Johnson
authors: Michael
authors: M
authors: St Andre
authors: James T
authors: JT
authors: Anderson
authors: Thomas
authors: T
authors: Kenney
authors: Sue
authors: S
authors: Chiparri
authors: Chris
authors: C
authors: McNally
authors: Edward
authors: E
authors: Kilbourne
authors: Catherine
authors: C
authors: Thompson
authors: Sunil
authors: S
authors: Nagpal
authors: Gregory
authors: G
authors: Weber
authors: Scott
authors: S
authors: Schelling
authors: Jane
authors: J
authors: Owens
authors: Carl A
authors: CA
authors: Morris
authors: Dennis
authors: D
authors: Powell
authors: Patrick R
authors: PR
authors: Verhoest
authors: Adam M
authors: AM
authors: Gilbert
mesh_terms: D045930:Anabolic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015415:Biomarkers; D002460:Cell Line; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis; D014280:Triglycerides / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D045930:Anabolic Agents; D015415:Biomarkers; D007211:Indoles; D011944:Receptors, Androgen; D014280:Triglycerides; D013739:Testosterone; D007986:Luteinizing Hormone