Discovery of potent and muscle selective androgen receptor modulators through scaffold modifications.

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILEAndrogen receptorKi (nM)3.27.422Details
4-[(7R,7AS)-7-HYDROXY-1,3-DIOXOTETRAHYDRO-1H-PYRROLO[1,2-C]IMIDAZOL-2(3H)-YL]-1-NAPHTHONITRILEAndrogen receptorEC 50 (nM)2.37.422Details
BMS-564929Androgen receptorKi (nM)1.47.422Details
BMS-564929Androgen receptorEC 50 (nM)0.77.422Details