Therapeutic Applications for Ligands of Retinoid Receptors
Scott M. Thacher, Jayasree Vasudevan and Roshantha A.S. Chandraratna
Affiliation: Allergan, 2525 DupontDrive, P.O. Box 19543, Irvine, CA 92623, USA
Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARa and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama . RXR-specific retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications.
Keywords: retinoid receptors, PAR PXR, steriod thyroid superfamily, nuclear hormone receptors, cancer, epithelial differentiation, immue system, inflammation, modulation, acne, psoriasis, photoaging, RXRs structure activity relationships, diabetes, hypothyroidism, gene regulatory, inverse agonists, retinoic acid 1 ATRA, 9 cic RA2, LG 1069, mucous membranes, dystrgulation, LG 100268 9, fetal malformations, headache, bone formation, histone acetyltransferase HAT, transcriptiional co repressors, RARs, nCoR, adapalene, tazarotene, ODC Inhibitory, PAR Panantagonism, cutaneous toxicity, TTNPB
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