Design, synthesis, and structure–activity relationship of podocarpic acid amides as liver X receptor agonists for potential treatment of atherosclerosis
| Autor: | Neelam Sharma, Weiguo Liu, Nancy S. Hayes, Steve Chen, Melba Hernandez, John G. Menke, Carl P. Sparrow, Michael Robins, James F. Dropinski, Michael J. Szymonifka, Lawrence F. Colwell, Sheo B. Singh, Charlotte Burton, Karen L. MacNaul |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Agonist medicine.drug_class Stereochemistry Clinical Biochemistry Receptors Cytoplasmic and Nuclear Pharmaceutical Science Carboxamide Biochemistry Chemical synthesis Mass Spectrometry Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Structure–activity relationship Liver X receptor Receptor Imide Molecular Biology Liver X Receptors Chemistry Organic Chemistry Phenanthrenes Atherosclerosis Orphan Nuclear Receptors Amides Rats DNA-Binding Proteins Nuclear receptor Area Under Curve Abietanes Molecular Medicine Chromatography Liquid |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 15:4574-4578 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2005.06.100 |
| Popis: | A series of podocarpic acid amides were identified as potent agonists for Liver X receptor alpha and beta subtypes, which are members of a nuclear hormone receptor superfamily that are involved in the regulation of a variety of metabolic pathways including cholesterol metabolism. We recently reported podocarpic acid anhydride and imide dimers as potent LXR agonists. Through parallel organic synthesis, we rapidly identified a series of new podocarpate leads with stable structures exemplified by adamantyl- and phenylcyclohexylmethyl-podocarpic acid amides (14 and 18). Compound 18 exhibited LXRalpha/beta 50/20 nM (binding affinity) and 33.7/35.3-fold receptor inductions. Synthesis, SAR, and biological activities of new podocarpate analogs are discussed. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect