Identification and structure-activity relationships of chromene-derived selective estrogen receptor modulators for treatment of postmenopausal symptoms
| Autor: | Ronald K. Russell, Martin Cousineau, Scott G. Lundeen, DoWon Hahn, Ramesh M. Kanojia, Nareshkumar F. Jain, David M. Ritchie, Muh-Tsann Lai, Guo Jian-Zhong, Xun Li, George F. Allan, Emmanuel Pacia, Jiayi Xu, Sean Peng, Fuyong Du, Zhihua Sui, Amy Musto, Michael Reuman |
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| Rok vydání: | 2009 |
| Předmět: |
Selective Estrogen Receptor Modulators
medicine.medical_specialty Ovariectomy Mammary gland Drug Evaluation Preclinical Estrogen receptor Pharmacology Endometrium Substrate Specificity Structure-Activity Relationship Drug Stability In vivo Internal medicine Cell Line Tumor Drug Discovery medicine Animals Humans Benzopyrans Bone Resorption Chemistry Uterus Epithelial Cells Organ Size Ligand (biochemistry) In vitro Rats Postmenopause medicine.anatomical_structure Endocrinology Cholesterol Receptors Estrogen Selective estrogen receptor modulator Cell culture Hot Flashes Vagina Molecular Medicine Female hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of medicinal chemistry. 52(23) |
| ISSN: | 1520-4804 |
| Popis: | As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R). |
| Databáze: | OpenAIRE |
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