Lv, WeiLiu, JinzhongLu, DeshunFlockhart, David A.Cushman, Mark2025-05-072025-05-072013Lv W, Liu J, Lu D, Flockhart DA, Cushman M. Synthesis of mixed (E,Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. J Med Chem. 2013;56(11):4611-4618. doi:10.1021/jm400364hhttps://hdl.handle.net/1805/47863The first synthesis of the tamoxifen metabolite norendoxifen is reported. This included syntheses of (E)-norendoxifen, (Z)-norendoxifen, and (E,Z)-norendoxifen isomers. (Z)-Norendoxifen displayed affinity for aromatase (Ki 442 nM), estrogen receptor-α (EC50 17 nM), and estrogen receptor-β (EC50 27.5 nM), while the corresponding values for (E)-norendoxifen were aromatase (Ki 48 nM), estrogen receptor-α (EC50 58.7 nM), and estrogen receptor-β (EC50 78.5 nM). Docking and energy minimization studies were performed with (E)-norendoxifen on aromatase, and the results provide a foundation for structure-based drug design. The oral pharmacokinetic parameters for (E,Z)-norendoxifen were determined in mice, and (Z)-norendoxifen was found to result in significantly higher plasma concentrations and exposures (AUC values) than (E)-norendoxifen. The affinities of both isomers for aromatase and the estrogen receptors, as well as the pharmacokinetic results, support the further development of norendoxifen and its analogues for breast cancer treatment.en-USPublisher PolicyAntineoplastic agentsAromatase inhibitorsEstrogen receptor modulatorsTamoxifenArticle