Structure-Based Design of Potent Retinoid X Receptor α Agonists
| Autor: | Aaron B. Miller, Steve Blanchard, Kate A. Dwornik, Dallas K. Croom, Robert T. Gampe, Tom G. Consler, James M. Lenhard, Olivia Ittoop, Valerie G. Montana, Randy K. Bledsoe, and Andrea Ayscue, Darryl Lynn Mcdougald, Curt D. Haffner, H. Eric Xu |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Models Molecular Agonist medicine.medical_specialty Receptors Retinoic Acid medicine.drug_class Stereochemistry Retinoid X receptor Crystallography X-Ray Ligands Transfection Cell Line Mice Radioligand Assay Structure-Activity Relationship Internal medicine Drug Discovery medicine Animals Humans Hypoglycemic Agents Potency Structure–activity relationship Retinoid Receptor Benzofurans Binding Sites Retinoid X receptor alpha Chemistry Stereoisomerism Lipid metabolism Haplorhini Lipids Rats Rats Zucker Retinoid X Receptors Endocrinology Acrylates Diabetes Mellitus Type 2 Molecular Medicine Transcription Factors |
| Zdroj: | Journal of Medicinal Chemistry. 47:2010-2029 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism. |
| Databáze: | OpenAIRE |
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