Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4‑[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6‑(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN)

Sulfonic
acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)­ethynyl]­benzoic
acid (bexarotene, 1) as well as seven novel and two reported
analogues of 6-(ethyl­(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)­amino)­nicotinic
acid (NEt-TMN) were synthesized and assessed for selective
retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved
for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor
pathways. All of the analogues in this study were evaluated for their
potential to bind RXR through modeling and then assayed in an RXR–RXR
mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated
transcriptional experiments. The EC50 profiles for these
unique analogues and their analogous effectiveness to inhibit proliferation
in CTCL cells relative to 1 suggest that these compounds
possess similar or even enhanced therapeutic potential. Several compounds
also displayed more selective RXR activation with minimal cross-signaling
of the retinoic acid receptor. These results suggest that modifications
of potent RXR agonists such as NEt-TMN can lead to improved
biological selectivity and potency compared with the known therapeutic.