117259-83-3Relevant academic research and scientific papers
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 (1995)
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.
Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase
Diaz, Philippe,Huang, Weize,Keyari, Charles M.,Buttrick, Brian,Price, Lauren,Guilloteau, Nicolas,Tripathy, Sasmita,Sperandio, Vanessa G.,Fronczek, Frank R.,Astruc-Diaz, Fanny,Isoherranen, Nina
, p. 2579 - 2595 (2016/04/10)
Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the exist
Compounds activating pharmacological effects of retinoids
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, (2008/06/13)
A compound represented by the formula (I) or (II) or a salt thereof wherein R1 represents hydrogen atom or a C1-6 alkyl group; R2 and R3 independently represent a hydrogen atom or a C1-6 alkyl group,
Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers
Umemiya, Hiroki,Fukasawa, Hiroshi,Ebisawa, Masayuki,Eyrolles, Laurence,Kawachi, Emiko,Eisenmann, Ghislaine,Gronemeyer, Hinrich,Hashimoto, Yuichi,Shudo, Koichi,Kagechika, Hiroyuki
, p. 4222 - 4234 (2007/10/03)
In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H- 10,11,12,13-tetrahydro-10,10,13,13,15-pentamethyldinaphtho[2,3-b][1,2- e]diazepin-7-yl)benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4- [5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]diazepin-11-yl]- benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR- antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.
Bridged bicyclic aromatic compounds and their use in modulating gene expression of retinoid receptors
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, (2008/06/13)
Bridged bicyclic aromatic compounds are provided having the structure STR1 wherein R1, R2, R3, R4, R5 and n are as defined herein. The novel compounds are useful for modulating gene expression of retinoic acid receptors, vitamin D receptors and thyroid receptors. Pharmaceutical compositions and methods for modulating gene expression are provided as well.
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.
