A three-dimensional pharmacophore model of known AR down-regulating agents (ARDAs) was generated from a training set of five compounds using the Catalyst/Hip Hop program on the basis of in vitro ARDAs EC₅₀ values. Four chemical features were identified included, one hydrophobic group, one ring aromatic group and two hydrogen bond acceptors. This model served as a template in virtual screening of the Maybridge and NCI databases from which we retrieved six and eleven compounds, respectively. Six of these compounds were shown to down-regulate the expression of AR in LNCaP cells and five inhibited LNCaP cell growth. Modifications of a lead compound yielded extremely potent inhibitors of LNCaP cell growth (IC_50s from 1.45 – 83.0 nM). To the best of our knowledge, these set of molecules are the first synthetic leads for AR down-regulation developed by pharmacophore-based drug design strategy and provide a novel class of anti-cancer agents.