We designed and synthesized 4,4'-(piperidin-4-ylidenemethylene)bisphenol derivatives as novel tunable estrogen receptor (ER) modulators. The introduction of hydrophobic substituents on the nitrogen atom of the piperidine ring enhanced ERa binding affinity. In addition, the introduction of four methyl groups adjacent to the piperidine ring nitrogen atom remarkably enhanced ERa binding affinity. N-Acetyl2,2,6,6-tetramethylpiperidine derivative 3b showed high ERa binding affinity, high MCF-7 cell proliferation inducing activity, and high metabolic stability in rat liver S9 fractions. (C) 2016 Elsevier Ltd. All rights reserved.