156910-40-6Relevant articles and documents
Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity
Dawson,Jong,Hobbs,Cameron,Chao,Pfahl,Lee -,Shroot,Pfahl
, p. 3368 - 3383 (2007/10/03)
The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (BARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three PAR subtypes or RXRα. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXRα activity and selectivity. In addition, the β-geranylidene and 20-methyl-(11E,13E)- dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8- tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXRα selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5- thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.
Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids
Boehm,Zhang,Badea,White,Mais,Berger,Suto,Goldman,Heyman
, p. 2930 - 2941 (2007/10/02)
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 (TTNPB) 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]benzoic acid (6b), is the first RXR-selective retinoid (designated as LGD1069) to enter clinical trials for cancer indications.
