Synthesis of mixed (E,Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities.

Abstract	The 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.
Authors	Wei Lv, Jinzhong Liu, Deshun Lu, David A Flockhart, Mark Cushman
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 11 Pg. 4611-8 (Jun 13 2013) ISSN: 1520-4804 [Electronic] United States
PMID	23731360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Aromatase Inhibitors Estrogen Receptor Modulators Estrogen Receptor alpha Estrogen Receptor beta N,N-didesmethyl-4-hydroxytamoxifen Tamoxifen
Topics	Administration, Oral Animals Antineoplastic Agents (chemical synthesis, chemistry, pharmacology) Aromatase Inhibitors (chemical synthesis, chemistry, pharmacology) Biological Availability Estrogen Receptor Modulators (chemical synthesis, chemistry, pharmacology) Estrogen Receptor alpha (metabolism) Estrogen Receptor beta (metabolism) Humans Mice Mice, Inbred NOD Mice, SCID Models, Molecular Protein Binding Stereoisomerism Structure-Activity Relationship Tamoxifen (analogs & derivatives, chemical synthesis, chemistry, pharmacology)

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