Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid

This review presents a historical overview of the discoveries of retinoic acid receptor (RAR) and retinoid X receptor (RXR) class- and subtype-selective synthetic retinoids. These synthetic retinoids are conformationally restricted by having aromatic rings in place of the tetraene bond systems of all-trans- and 9-cis-retinoic acids. Events leading to the design and synthesis of such retinoid transcriptional agonists as RAR subtype beta,gamma-selective 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naph-thalenecarboxylic acid (TTNN), the RARgamma-selective Z-oxime of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbonyl)-2-naphthalenecarboxylic acid (SR11254), RAR-selective 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid (TTAB), RXR-selective 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-cyclopropyl] benzoic acid (SR11246), RXR-selective 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-methylpropenyl]benzoic acid (SR11345), and RARgamma-selective retinoid transcriptional antagonist 2-(6-carboxy-2-naphthalenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiolane (SR11253) are described.