Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids

Abstract

Two series of potent retinoid X receptor (RXR)-selective compounds were designed and synthesized based upon recent observation that (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1- propenyl]benzoic acid (TTNBP) binds and transactivates only the retinoic acid receptor (RAR) subtypes whereas (E)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydro-2-naphthalenyl)-1-propenyl]benzoic acid (3-methyl TTNPB) binds and transactivates both the RAR and RXR subfamilies. Addition of functional groups such as methyl, chloro, bromo, or ethyl to the 3 position of the tetrahydronaphthalene moiety of 4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid (5a) and 4-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (6a) results in compounds which elicit potent and selective activation of the RXR class. Such RXR-selective compounds offer pharmacological tools for elucidating the biological role of the individual retinoid receptors with which they interact. Activation profiles in cotransfection and competitive binding assays as well as molecular modeling calculations demonstrate critical structural determinants that confer selectivity for members of the RXR subfamily. The most potent compound of these series, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]ben zoi c acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

“…54 Increased binding affinity from retinoids exhibiting increased rigidity has been reported for a number of other synthetic retinoids in both the RARs and RXRs. 55,56 EC19 exhibited atypical retinoid binding according to simulation due to its meta-carboxylate substituent. This resulted in the sacrifice of a key hydrogen bond to the polar cluster at the bottom of the pocket, and also served to give non-ideal hydrophobic interactions around the hydrophobic region in RARα and RARγ.…”

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome

“…Bexarotene is highly selective for the RXRs, and was the first 'rexinoid' to undergo clinical development. [63][64][65] The drug has received EMEA approval in Europe for the treatment of skin manifestations in advanced CTCL. 66 Although the precise mechanisms are unknown, in vitro studies have shown that bexarotene can inhibit growth in tumour cell lines and cause in vivo tumour regression in animal models: the drug also stimulates apoptosis.…”

Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide Fixation and Preliminary PET Imaging

“…2 Defective retinoid signaling and deficiency of apolipoprotein E (ApoE) are closely associated with Alzheimer's disease (AD). 3 Bexarotene (4-[1- (3,5,5,8,8-pentamethyltetralin-2-yl)-ethenyl]benzoic acid, Figure 1), an FDA-approved selective RXR agonist, 4 has recently been demonstrated to induce clearance of β-amyloid from the brains of murine AD models through activation of the APOE gene, which is the most indicative genetic risk factor for late-onset AD. 5 In vitro and in vivo studies also suggest that bexarotene is acting on RXRs, and not directly on β-amyloid or by compromising the blood−brain barrier.…”