Design, synthesis and structure–activity relationship of novel RXR-selective modulators

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)

“…Novel aza-retinoids, exemplified by compound 4 29 , as well as amide retinoids 30 have been described. RXR agonists based on aryl-trienoic acid compounds either unbranched 31 , or locked with one 32 or multiple-fused 33 ring systems were developed by Boehm and co-workers, of which 5 33 demonstrates the latter. Our group has reported that the addition of a single fluorine atom ortho to the carboxylic acid group of 1 , giving compound 6 34 , and the addition of two fluorine atoms, giving compound 7 35 , increases RXR agonism in human colon cancer cell lines, Caco-2 and HCT-116, respectively.…”

Retinoid X Receptor Antagonists

“…Compound 6 binds to RXRα at low concentrations and shows RXR antagonist activity, but a synergistic effect with an agonist of PPARγ was also found. Subsequently, 7 , which has a ring structure at the 6 and 7 positions of the trienoic acid structure of 6 , and 8 , which has another ring structure at the 4 and 5 positions of 7 , were created [47,48]. Compound 8 shows more potent RXR antagonist activity than 6 [47].…”

“…Subsequently, 7 , which has a ring structure at the 6 and 7 positions of the trienoic acid structure of 6 , and 8 , which has another ring structure at the 4 and 5 positions of 7 , were created [47,48]. Compound 8 shows more potent RXR antagonist activity than 6 [47]. Their K i values for RXRα in the presence of [ 3 H]9- cis retinoic acid are 3 nM ( 6 ), 9.9 nM ( 7 ), and 3 nM ( 8 ).…”

“…Their K i values for RXRα in the presence of [ 3 H]9- cis retinoic acid are 3 nM ( 6 ), 9.9 nM ( 7 ), and 3 nM ( 8 ). Although the IC 50 values toward RXRα in reporter assay using CV-1 cells were also reported as 8 nM ( 6 ), 10.3 nM ( 7 ), and 8 nM ( 8 ), the RXR agonist and the concentration used were not mentioned [45,46,47]. Since these RXR ligands activate specific heterodimers, the authors refer to the compounds as “selective RXR modulators” [45].…”

Inside Cover: Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor‐Selective Agonists: Novel Halogenated Analogues of 4‐[1‐(3,5,5,8,8‐Pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethynyl]benzoic Acid (Bexarotene) (ChemMedChem 9/2012)

“…Substituting pyridine for one of the aromatic rings has led to several analogs of 1 , such as compound 6 [25] , and analogs of 1 possessing unsaturation in the aliphatic ring, as in compound 7 [26] , have also been reported. Studies describing the development of selective RXR agonists containing aryl-trienoic acid moieties, either alone [27] , or locked by one [28] or two [29] ring systems, were disclosed by Boehm et al, for which compound 8 is representative of the latter. Acetal 9 [30] and compound 10 [7] are both selective, potent RXR agonists, with the latter serving as a model to design a potent RXR antagonist.…”