Abstract
Retinoid X receptor (RXR) agonists are interesting candidates for the treatment of metabolic syndrome. 9-Cis-retinoic acid (9cRA: 1) is a natural RXR agonist, that also works as a retinoic acid receptor (RAR) agonist. This fact prompted us to study the structure-activity relationship (SAR) of RXR agonists derived from 1. Though 3 and 4, in which the cyclohexene part of 1 is replaced with bulkier hydrophobic moieties, show RXR-selective agonistic activity, some analogs containing other ring structures show RAR agonistic activity. Thus, we were interested in establishing what kind of ring skeleton is required for RXR-selective agonistic activity. In this study, we systematically prepared 5 and 6, in which the cyclohexene ring of 1 is replaced with various cyclic terpenoid moieties, and evaluated their RXR and RAR agonistic activities. Our previously reported CsF-promoted Stille coupling reaction was employed as a key step for the comprehensive synthesis of 5 and 6. The results of transcriptional assay showed that compounds 5b-f, which possess a menthane skeleton, exhibit RXR-selective agonistic activity. These results should be helpful for the design of superior RXR-selective agonists based on the structure of 1.
Original language | English |
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Pages (from-to) | 2939-2949 |
Number of pages | 11 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 19 |
Issue number | 9 |
DOIs | |
Publication status | Published - May 1 2011 |
Externally published | Yes |
Keywords
- 9-cis-Retinoic acid
- Agonist
- RAR
- RXR
- Rexinoids
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry