Allan George, Lai Muh-Tsann, Sbriscia Tifanie, Linton Olivia, Haynes-Johnson Donna, Bhattacharjee Sheela, Dodds Robert, Fiordeliso James, Lanter James, Sui Zhihua, Lundeen Scott
Reproductive Therapeutics, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202 South, Room B-115, Raritan, NJ 08869, USA.
J Steroid Biochem Mol Biol. 2007 Jan;103(1):76-83. doi: 10.1016/j.jsbmb.2006.07.006. Epub 2006 Oct 17.
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.
描述了JNJ - 26146900的药理活性。JNJ - 26146900是一种非甾体雄激素受体（AR）配体，在大鼠中具有组织选择性活性。该化合物在AR活性的体外和体内模型中进行了评估。它以400nM的K(i)与大鼠AR结合，并在基于细胞的体外试验中作为纯雄激素拮抗剂发挥作用。其体外特征与雄激素拮抗剂比卡鲁胺（康士得）相似。在完整大鼠中，JNJ - 26146900降低腹侧前列腺重量，口服效力（ED(50)）为20 - 30mg/kg，同样与比卡鲁胺相当。JNJ - 26146900在邓恩大鼠模型中可预防前列腺肿瘤生长，在10mg/kg剂量时最大程度抑制生长。在人前列腺癌的CWR22 - LD1小鼠异种移植模型中，它显著减缓了肿瘤生长。对老年雄性大鼠进行了测试，以评估其预防去势后骨质流失和瘦体重丢失的能力。给药6周后，通过微型计算机断层扫描分析测量，去势大鼠与完整载体处理大鼠相比，骨体积减少了33%，概率（P）小于0.05。在30mg/kg剂量下，JNJ - 26146900显著减少了去势诱导的胫骨骨质流失，以下参数表明了这一点：骨体积、小梁连接性、小梁数量和小梁间距。去势后骨矿物质密度从229±34mg/cm³的羟基磷灰石降至166±26mg/cm³，而JNJ - 26146900治疗使其维持在194±20mg/cm³（相对于单独去势，P<0.05）。使用磁共振成像发现，该化合物可部分预防去势诱导的瘦体重丢失。我们的数据表明，选择性雄激素受体调节剂（SARMs）在维持前列腺癌治疗效果的同时，对骨骼和肌肉具有合成代谢作用的潜力。
