Synthesis of Mixed (E,Z)-, (E)-, and (Z)-Norendoxifen with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities
| Autor: | Mark Cushman, Wei Lv, Jinzhong Liu, Deshun Lu, David A. Flockhart |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular medicine.medical_specialty Metabolite Administration Oral Biological Availability Estrogen receptor Antineoplastic Agents Stereoisomerism Mice SCID Pharmacology Article Mice Structure-Activity Relationship chemistry.chemical_compound Estrogen Receptor Modulators Mice Inbred NOD Internal medicine Drug Discovery medicine Animals Estrogen Receptor beta Humans Aromatase Estrogen receptor beta biology Aromatase Inhibitors Norendoxifen Estrogen Receptor alpha Tamoxifen Endocrinology chemistry biology.protein Molecular Medicine Estrogen receptor alpha Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 56:4611-4618 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400364h |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|