Since the isolation and identification of the retinoid X receptor (RXR) as a member of the
nuclear receptor (NR) superfamily in 1990, its analysis has ushered in a new understanding of physiological
regulation by nuclear receptors, and novel methods to identify other unknown and orphan receptors.
Expression of one or more of the three isoforms of RXR—α, β, and γ—can be found in every
human cell type. Biologically, RXR plays a critical role through its ability to partner with other nuclear
receptors. RXR is able to regulate nutrient metabolism by forming “permissive” heterodimers with peroxisome
proliferator-activated receptor (PPAR), liver-X-receptor (LXR), farnesoid X receptor (FXR),
pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which function when ligands
are bound to one or both of the heterodimer partners. Conversely, RXR is able to form “nonpermissive”
heterodimers with vitamin D receptor (VDR), thyroid receptor (TR) and retinoic acid receptor (RAR),
which function only in the presence of vitamin D, T3 and retinoic acid, respectively. Furthermore, RXR
can form homodimers in the presence of a selective agonist, or rexinoid, to regulate gene expression and
to either inhibit proliferation or induce apoptosis in human cancers. Thus, over the last 25 years there
have been several reports on the design and synthesis of small molecule rexinoids. This review summarizes
the synthetic methods for several of the most potent rexinoids thus far reported.