title: A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.
abstract: 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.
authors.affiliation: Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202 South, Room B-115, Raritan, NJ 08869, USA. allang090864@yahoo.com
authors.forename: George
authors.initials: G
authors.lastname: Allan
authors.forename: Muh-Tsann
authors.initials: MT
authors.lastname: Lai
authors.forename: Tifanie
authors.initials: T
authors.lastname: Sbriscia
authors.forename: Olivia
authors.initials: O
authors.lastname: Linton
authors.forename: Donna
authors.initials: D
authors.lastname: Haynes-Johnson
authors.forename: Sheela
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Robert
authors.initials: R
authors.lastname: Dodds
authors.forename: James
authors.initials: J
authors.lastname: Fiordeliso
authors.forename: James
authors.initials: J
authors.lastname: Lanter
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
authors.forename: Scott
authors.initials: S
authors.lastname: Lundeen
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists; D000818:Animals; D001823:Body Composition; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000473:pathology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009919:Orchiectomy / Q000009:adverse effects*; D011467:Prostate / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D007211:Indoles; C517123:JNJ-26146900