Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.
Article Details
- CitationCopy to clipboard
Li JJ, Sutton JC, Nirschl A, Zou Y, Wang H, Sun C, Pi Z, Johnson R, Krystek SR Jr, Seethala R, Golla R, Sleph PG, Beehler BC, Grover GJ, Fura A, Vyas VP, Li CY, Gougoutas JZ, Galella MA, Zahler R, Ostrowski J, Hamann LG
Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.
J Med Chem. 2007 Jun 28;50(13):3015-25. Epub 2007 Jun 7.
- PubMed ID
- 17552509 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILE Androgen receptor Ki (nM) 3.2 7.4 22 Details 4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILE Androgen receptor EC 50 (nM) 2.3 7.4 22 Details BMS-564929 Androgen receptor Ki (nM) 1.4 7.4 22 Details BMS-564929 Androgen receptor EC 50 (nM) 0.7 7.4 22 Details