ArticleJournal of medicinal chemistry2014
Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 21 citations in OpenAlex.
- Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics.The Journal of biological chemistry · 2023Article
- An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene.International journal of molecular sciences · 2022Article
- Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers.Journal of medicinal chemistry · 2022Article
- Increased Molecular Flexibility Widens the Gap betweenACS medicinal chemistry letters · 2022Article
- Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).International journal of molecular sciences · 2021Article
- Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide.Biochemistry · 2021Article
- A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences.ACS medicinal chemistry letters · 2019Article
- A review of the molecular design and biological activities of RXR agonists.Medicinal research reviews · 2019Review
- Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention.Current topics in medicinal chemistry · 2017Review
- Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers.Journal of medicinal chemistry · 2015Article
- Pharmacogenomic analysis of retinoic-acid induced dyslipidemia in congenic rat model.Lipids in health and disease · 2014Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
(2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.