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)

Abstract

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 EC 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.

Drug discovery for remyelination and treatment of MS

“…Indeed, a clinical trial using another pan‐RXR agonist, already approved for the treatment of cutaneous T‐cell lymphoma (Pileri, Delfino, Grandi, & Pimpinelli, ), bexarotene, is in preparation for an MS trial. Both 9‐ cis ‐retinoic acid and bexarotene are nonspecific with respect to agonising RXR receptors α, β, and γ, and may have side effects that limit their long‐term use, which has driven studies to identify isoform‐specific agonists of RXR subtypes (Heck et al, ). However, it is possible that pan‐RXR activation may actually have beneficial effects in promoting remyelination.…”

A review of the molecular design and biological activities of RXR agonists

“…The molecules also presented, at least, a twofold preference for activating RXR/RXRE transcription vs SREBPs. 109 More encouraging, all the ligands presented 20% the RAR activation of 1 (which was 100%) and 2 (~30%).…”

“…For example, the RXR‐mediated transcriptional activation in HCT‐116 cells at 100 nM was ~150% for 28 to 30 (the control, molecule 2 , was 100%). The molecules also presented, at least, a twofold preference for activating RXR/RXRE transcription vs SREBPs . More encouraging, all the ligands presented 20% the RAR activation of 1 (which was 100%) and 2 (~30%).…”

“…Compounds 26 to 31 (Figure ) were developed by Heck et al and their potential for causing hypertriglyceridemia and inhibit cancer cell proliferation, and mutagenicity were evaluated. Among the prepared molecules, the rexinoids 26 (EC 50 = 7.9 ± 0.4 nM), 27 (EC 50 = 13.8 ± 1.5 nM), 28 (EC 50 = 40.9 ± 0.6 nM), 29 (EC 50 = 18.2 ± 0.4 nM), and 31 (EC 50 = 33.8 ± 0.1 nM) were found to possess lower EC 50 than compound 2 (EC 50 = 52 ± 2.1 nM) in a RXR mammalian two‐hybrid assay using HCT‐116 colon cancer cells.…”

“…The authors also found that the modification in the acid domain of the RXR agonists did not have significant influence on permissive RXR/PPARγ and RXR/LXRα activation (<60% of 2) 107. Unfortunately, 25 was reported to cause several of the side effects observed with 2 such as increase in liver weight, cholesterol, and triglyceride levels [108][109][110]. However, the obtained results may be useful for the development of RXR agonists with better bioavailability since RXR agonists are lipophilic molecules, and their pharmacokinetics characteristics are not optimal 107.…”