The pharmacological activity of
JNJ-26146900 is described.
JNJ-26146900 is a nonsteroidal
androgen receptor (AR)
ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure
androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the
androgen antagonist bicalutamide (
Casodex). In intact rats,
JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of
bicalutamide.
JNJ-26146900 prevented prostate
tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed
tumor growth significantly in a CWR22-LD1 mouse xenograft model of human
prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following
orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg,
JNJ-26146900 significantly reduced
castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of
hydroxyapatite to 166+/-26mg/cm(3) following
orchidectomy, and was maintained at 194+/-20mg/cm(3) with
JNJ-26146900 treatment (P<0.05 relative to
orchidectomy alone). Using magnetic resonance imaging, the compound was found to partially prevent
orchidectomy-induced loss of lean body mass. Our data show that selective
androgen receptor modulators (SARMs) have the potential for
anabolic effects on bone and muscle while maintaining therapeutic efficacy in
prostate cancer.