|
Effective potency in transcriptional activation assay in CV-1 cells expressing Retinoid X receptor RXR beta
|
Mus musculus
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Dissociation constant for binding to Retinoic acid receptor RXR-alpha
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and characterization of a new RXR agonist based on the 6-tert-butyl-1,1-dimethylindanyl structure.
Year : 2002
Volume : 12
Issue : 18
First Page : 2607
Last Page : 2609
Authors : Domínguez B, Vega MJ, Sussman F, de Lera AR.
Abstract : A new ligand for RXR is described, which is based on a 6-tert-butyl-1,1-dimethylindanyl skeleton as bioisostere of the hydrophobic retinoid region. The Stille cross-coupling reaction allowed the attachment of the polyene side chain to the indanyl ring. Docking studies were carried out to explain the RXR binding profile of this analogue.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR alpha
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Selective activity towards retinoic acid receptor-beta
|
Homo sapiens
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR beta
|
None
|
282.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Selective activity towards retinoic acid receptor-gamma
|
Homo sapiens
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Transcriptional activation in CV-1 cells expressing Retinoic acid receptor RAR gamma
|
None
|
648.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Effective concentration against retinoid receptor isoform (RXR alpha) expressed in CV-1 cells
|
None
|
33.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Inhibition of [3H]9-cis-RA binding to baculovirus expressed retinoid receptor RXR alpha
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Selective activity towards retinoid X receptor-alpha
|
Homo sapiens
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR alpha
|
None
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Inhibition of [3H]9-cis-RA binding to RXR alpha receptor
|
None
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Selective activity towards retinoid X receptor-beta
|
Homo sapiens
|
5.9
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Ability to activate gene expression at Retinoic acid receptor RXR-alpha was evaluated in a cotransfection assay.
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Effective concentration against retinoid receptor isoform (RXR beta) expressed in CV-1 cells
|
None
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Inhibition of [3H]9-cis-RA binding to baculovirus expressed retinoid receptor RXR beta
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR beta
|
None
|
24.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Inhibition of [3H]9-cis-RA binding to RXR beta receptor
|
None
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Selective activity towards retinoid X receptor-gamma
|
Homo sapiens
|
8.3
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Effective concentration against retinoid receptor isoform (RXR gamma) expressed in CV-1 cells
|
None
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Inhibition of [3H]9-cis-RA binding to baculovirus expressed retinoid receptor RXR gamma
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids.
Year : 1994
Volume : 37
Issue : 18
First Page : 2930
Last Page : 2941
Authors : Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E, Suto CM, Goldman ME, Heyman RA.
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.
|
Transcriptional activation in CV-1 cells expressing retinoid X receptor RXR gamma
|
None
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Inhibition of [3H]9-cis-RA binding to RXR gamma receptor
|
None
|
29.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent conformationally restricted retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 21
First Page : 2747
Last Page : 2752
Authors : Farmer LJ, Lin Zhi, Susan Jeong, Adam Kallel E, Croston G, Flatten KS, Heyman RA, Nadzan AM
|
Effective potency in transcriptional activation assay in CV-1 cells expressing Retinoid X receptor RXR alpha
|
Homo sapiens
|
28.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Ability to bind directly to Retinoic acid receptor RXR-alpha was evaluated in a competitive binding assay.
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Inhibition of [3H]9-cis-RA binding to Retinoid X receptor RXR alpha
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Effective concentration against Retinoic acid receptor RXR-alpha
|
None
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) 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 RAR subtypes or RXR alpha. 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 RXR alpha activity and selectivity. In addition, the beta-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. RXR alpha 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.
|
Transcriptional activity was evaluated in CV-1 cells transfected with expression vector for Retinoic acid receptor RXR-alpha
|
None
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Binding affinity towards recombinantly expressed Retinoic acid receptor RXR-alpha in baculoviral system, by using 5 nM [3H]targretin in a competitive binding assay
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Ability to activate gene expression at Retinoic acid receptor RXR-beta was evaluated in a cotransfection assay.
|
None
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Binding affinity to Retinoic acid receptor RXR-beta was determined in a competitive binding assay.
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Inhibition of [3H]-9-cis-RA binding to Retinoid X receptor RXR beta
|
Mus musculus
|
21.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Effective concentrations against Retinoic acid receptor RXR-beta
|
None
|
112.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) 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 RAR subtypes or RXR alpha. 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 RXR alpha activity and selectivity. In addition, the beta-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. RXR alpha 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.
|
Transcriptional activity was evaluated in CV-1 cells transfected with expression vector for Retinoic acid receptor RXR-beta
|
None
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Binding affinity towards recombinantly expressed Retinoic acid receptor RXR-beta in baculoviral system, by using 5 nM [3H]targretin in a competitive binding assay
|
None
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Ability to activate gene expression at Retinoic acid receptor RXR-gamma was evaluated in a cotransfection assay.
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Effective potency in transcriptional activation assay in CV-1 cells expressing Retinoid X receptor RXR gamma
|
Mus musculus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Binding affinity to Retinoic acid receptor RXR-gamma was evaluated in a competitive binding assay.
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells.
Year : 1995
Volume : 38
Issue : 16
First Page : 3146
Last Page : 3155
Authors : Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA.
Abstract : Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
|
Inhibition of [3H]9-cis-RA binding to Retinoid X receptor RXR gamma
|
Mus musculus
|
29.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of potent retinoid X receptor ligands
Year : 1997
Volume : 7
Issue : 18
First Page : 2393
Last Page : 2398
Authors : Farmer LJ, Jeong S, Kallel E, Canan Koch SS, Croston GE, Flatten KS, Heyman RA, Nadzan AM
|
Effective concentrations against Retinoic acid receptor RXR-gamma
|
None
|
122.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity.
Year : 1995
Volume : 38
Issue : 17
First Page : 3368
Last Page : 3383
Authors : Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao WR, Pfahl M, Lee MO, Shroot B, Pfahl M.
Abstract : The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) 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 RAR subtypes or RXR alpha. 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 RXR alpha activity and selectivity. In addition, the beta-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. RXR alpha 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.
|
Transcriptional activity was evaluated in CV-1 cells transfected with expression vector for Retinoic acid receptor RXR-gamma
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Binding affinity towards recombinantly expressed Retinoic acid receptor RXR-gamma in baculoviral system, by using 5 nM [3H]targretin in a competitive binding assay
|
None
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells.
Year : 1999
Volume : 42
Issue : 4
First Page : 742
Last Page : 750
Authors : Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM.
Abstract : A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
|
Binding affinity towards Retinoic acid receptor RXR-gamma
|
Homo sapiens
|
75.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Selective activity towards retinoic acid receptor-alpha
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.
Year : 1997
Volume : 40
Issue : 26
First Page : 4222
Last Page : 4234
Authors : Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H.
Abstract : 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.
|
Binding affinity towards cRAR-beta-2 receptor by displacing 0.82 nM 3[H]all-trans-RA
|
None
|
550.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Binding affinity towards cRAR-beta-2 receptor by displacing 1.1 nM 3[H]-9-cis-RA
|
None
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and receptor binding affinity of conformationally restricted retinoic acid analogues
Year : 1997
Volume : 7
Issue : 17
First Page : 2313
Last Page : 2318
Authors : Wong MF, Repa JJ, Clagett-Dame M, Curley RW
|
Transactivation of Gal4-LBD fused mouse RXRalpha (218 to 467) transfected in african green monkey CV1 cells assessed as luciferase activity at after 6 hrs by Dual-light chemiluminescent assay
|
Mus musculus
|
40.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Highly twisted adamantyl arotinoids: synthesis, antiproliferative effects and RXR transactivation profiles.
Year : 2009
Volume : 44
Issue : 6
First Page : 2434
Last Page : 2446
Authors : Pérez-Rodríguez S, Ortiz MA, Pereira R, Rodríguez-Barrios F, de Lera AR, Piedrafita FJ.
Abstract : Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARbeta,gamma) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2'-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.
|
Agonist activity at human recombinant Gal4-tagged RXRalpha expressed in human Caco-2 cells assessed as receptor homodimerization after 24 hrs by mammalian two hybrid assay
|
Homo sapiens
|
52.0
nM
|
|
Journal : J. Med. Chem.
Title : 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).
Year : 2009
Volume : 52
Issue : 19
First Page : 5950
Last Page : 5966
Authors : Wagner CE, Jurutka PW, Marshall PA, Groy TL, van der Vaart A, Ziller JW, Furmick JK, Graeber ME, Matro E, Miguel BV, Tran IT, Kwon J, Tedeschi JN, Moosavi S, Danishyar A, Philp JS, Khamees RO, Jackson JN, Grupe DK, Badshah SL, Hart JW.
Abstract : This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.
|
Displacement of [3H]9-cis-retinoic acid form human RXRalpha expressed in human Caco-2 cells after 16 hrs
|
Homo sapiens
|
21.0
nM
|
|
Journal : J. Med. Chem.
Title : 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).
Year : 2009
Volume : 52
Issue : 19
First Page : 5950
Last Page : 5966
Authors : Wagner CE, Jurutka PW, Marshall PA, Groy TL, van der Vaart A, Ziller JW, Furmick JK, Graeber ME, Matro E, Miguel BV, Tran IT, Kwon J, Tedeschi JN, Moosavi S, Danishyar A, Philp JS, Khamees RO, Jackson JN, Grupe DK, Badshah SL, Hart JW.
Abstract : This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.
|
Agonist activity at RXRalpha by luciferase reporter gene assay
|
None
|
19.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation.
Year : 2010
Volume : 20
Issue : 17
First Page : 5139
Last Page : 5142
Authors : Fujii S, Ohsawa F, Yamada S, Shinozaki R, Fukai R, Makishima M, Enomoto S, Tai A, Kakuta H.
Abstract : Retinoid X receptors (RXRs) function as homo- or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 microM. The order of agonistic activity toward both PPARgamma/RXRalpha and LXRalpha/RXRalpha was the same as it was for RXR, that is, 11>10>12. These results should be useful for the development of RXR agonists with improved bioavailability.
|
Agonist activity at human RXRalpha LBD by cell based luciferase reporter gene assay
|
Homo sapiens
|
2.7
nM
|
|
Journal : J. Med. Chem.
Title : Identification of diaryl ether-based ligands for estrogen-related receptor α as potential antidiabetic agents.
Year : 2011
Volume : 54
Issue : 3
First Page : 788
Last Page : 808
Authors : Patch RJ, Searle LL, Kim AJ, De D, Zhu X, Askari HB, O'Neill JC, Abad MC, Rentzeperis D, Liu J, Kemmerer M, Lin L, Kasturi J, Geisler JG, Lenhard JM, Player MR, Gaul MD.
Abstract : Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.
|
Agonist activity at RXRalpha transfected in human COS1 cells after 18 hrs by luciferase reporter gene transactivation assay
|
None
|
20.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Modification at the Lipophilic Domain of RXR Agonists Differentially Influences Activation of RXR Heterodimers.
Year : 2010
Volume : 1
Issue : 9
First Page : 521
Last Page : 525
Authors : Ohsawa F, Morishita K, Yamada S, Makishima M, Kakuta H.
Abstract : RXR permissive heterodimers are reported to be activated differently depending upon the chemical structure of RXR agonists, but the relationship of agonist structure to differential heterodimer activation has not been explored in detail. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid, NEt-3IP) and evaluated the RXR-, PPAR/RXR-, and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analogue (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analogue (5i) and n-propoxy analogue (5k) but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia or type 2 diabetes.
|
SANGER: Inhibition of human SIG-M5 cell growth in a cell viability assay.
|
Homo sapiens
|
0.6582
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DK-MG cell growth in a cell viability assay.
|
Homo sapiens
|
51.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EKVX cell growth in a cell viability assay.
|
Homo sapiens
|
164.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-13 cell growth in a cell viability assay.
|
Homo sapiens
|
485.1
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MEL-HO cell growth in a cell viability assay.
|
Homo sapiens
|
531.05
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MG-63 cell growth in a cell viability assay.
|
Homo sapiens
|
788.8
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MV-4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
452.56
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Transactivation of human RXRalpha transfected in human 293 cells after 48 hrs by dual-luciferase reporter gene assay
|
Homo sapiens
|
149.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a small molecular compound simultaneously targeting RXR and HADC: design, synthesis, molecular docking and bioassay.
Year : 2013
Volume : 23
Issue : 13
First Page : 3891
Last Page : 3895
Authors : Chen GL, Wang LH, Wang J, Chen K, Zhao M, Sun ZZ, Wang S, Zheng HL, Yang JY, Wu CF.
Abstract : Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for anti-cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we have designed and synthesized a novel compound which targets both RXR and HADC. This dual-targeting agent is derived from bexarotene and suberoylanilide hydroxamic acid (SAHA), prototypical RXR agonist and HDAC inhibitor, respectively. Molecular docking studies demonstrate that this agent has a relatively strong affinity to RXR and HADC. Importantly, it presents the potentials of activation of RXR and inhibition of HDAC in both cell-free and whole-cell assays, and displays anti-proliferative effect on representative cancer cell lines and drug-resistant cancer cell lines.
|
Agonist activity at RXRalpha in rat RK3E cells assessed as transcriptional activation by luciferase reporter gene assay
|
Rattus norvegicus
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Year : 2014
Volume : 22
Issue : 1
First Page : 178
Last Page : 185
Authors : Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
|
Binding affinity to human RXRalpha ligand binding domain by fluorescence assay
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.
Year : 2014
Volume : 22
Issue : 1
First Page : 178
Last Page : 185
Authors : Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
|
Binding affinity to human RXR-alpha-ligand binding domain homodimers by fluorescence quenching method
|
Homo sapiens
|
26.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Agonist activity at Gal4-fused human RXR-alpha expressed in HEK293 cells assessed as receptor-mediated transcriptional activity treated 24 hrs after transfection measured 48 hrs post-transfection by dual luciferase reporter assay
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Anticancer activity against N-methylnitrosurea-induced mammary cancer in Sprague-Dawley rat assessed as decrease in proliferation index at 150 mg/kg administered through diet for 7 days by BrdU incorporation assay
|
Rattus norvegicus
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.
Year : 2014
Volume : 57
Issue : 12
First Page : 5370
Last Page : 5380
Authors : Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.
|
Agonist activity at RXRalpha (unknown origin) expressed in COS1 cells incubated for 18 hrs by luciferase reporter gene assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists.
Year : 2015
Volume : 6
Issue : 3
First Page : 334
Last Page : 338
Authors : Kobayashi T, Furusawa Y, Yamada S, Akehi M, Takenaka F, Sasaki T, Akahoshi A, Hanada T, Matsuura E, Hirano H, Tai A, Kakuta H.
Abstract : RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E max = 55%) showed a blood concentration higher than its E max after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [(11)C]1a, [(11)C]2a and fluorinated derivatives [(18)F]1b, [(18)F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a.
|
Agonist activity at RXRalpha LBD (unknown origin) expressed in CV1 cells
|
Homo sapiens
|
118.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers.
Year : 2015
Volume : 58
Issue : 19
First Page : 7763
Last Page : 7774
Authors : Atigadda VR, Xia G, Deshpande A, Wu L, Kedishvili N, Smith CD, Krontiras H, Bland KI, Grubbs CJ, Brouillette WJ, Muccio DD.
Abstract : (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.
|
Agonist activity at histidine-tagged ligand binding domain of human RXRalpha expressed in Escherichia coli BL21 (DE3) by luciferase reporter gene assay
|
Homo sapiens
|
31.62
nM
|
|
Journal : J. Med. Chem.
Title : Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.
Year : 2016
Volume : 59
Issue : 3
First Page : 1232
Last Page : 1238
Authors : Sundén H, Schäfer A, Scheepstra M, Leysen S, Malo M, Ma JN, Burstein ES, Ottmann C, Brunsveld L, Olsson R.
Abstract : The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
|
Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha/Nurr1 (unknown origin) expressed in HEK293T cells by BRET2 assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.
Year : 2016
Volume : 59
Issue : 3
First Page : 1232
Last Page : 1238
Authors : Sundén H, Schäfer A, Scheepstra M, Leysen S, Malo M, Ma JN, Burstein ES, Ottmann C, Brunsveld L, Olsson R.
Abstract : The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
|
Agonist activity at Renilla luciferase/GFP2-tagged RXRalpha homodimer (unknown origin) expressed in HEK293T cells by BRET2 assay
|
Homo sapiens
|
31.62
nM
|
|
Journal : J. Med. Chem.
Title : Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation.
Year : 2016
Volume : 59
Issue : 3
First Page : 1232
Last Page : 1238
Authors : Sundén H, Schäfer A, Scheepstra M, Leysen S, Malo M, Ma JN, Burstein ES, Ottmann C, Brunsveld L, Olsson R.
Abstract : The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
|
Agonist activity at RXRaplha (unknown origin)
|
Homo sapiens
|
33.0
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Agonist activity at RXRbeta (unknown origin)
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Agonist activity at RXRgamma (unknown origin)
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Partial agonist activity at recombinant human GAL4-DBD-fused LXRalpha-LBD expressed in HEK293T cells measured after 12 to 14 hrs by dual-glo luciferase reporter gene assay
|
Homo sapiens
|
196.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators.
Year : 2017
Volume : 27
Issue : 5
First Page : 1193
Last Page : 1198
Authors : Heitel P, Achenbach J, Moser D, Proschak E, Merk D.
Abstract : In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.
|
Partial agonist activity at recombinant human GAL4-DBD-fused LXRbeta-LBD expressed in HEK293T cells measured after 12 to 14 hrs by dual-glo luciferase reporter gene assay
|
Homo sapiens
|
434.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators.
Year : 2017
Volume : 27
Issue : 5
First Page : 1193
Last Page : 1198
Authors : Heitel P, Achenbach J, Moser D, Proschak E, Merk D.
Abstract : In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.
|
Agonist activity at human RXRalpha expressed in African green monkey CV1 cells
|
Homo sapiens
|
33.0
nM
|
|
Journal : MedChemComm
Title : Scaffold hopping from synthetic RXR modulators by virtual screening and <i>de novo</i> design.
Year : 2018
Volume : 9
Issue : 8
First Page : 1289
Last Page : 1292
Authors : Merk D, Grisoni F, Friedrich L, Gelzinyte E, Schneider G.
Abstract : The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated <i>de novo</i> design, we identified novel RXR ligands exhibiting innovative molecular frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.
|
Agonist activity at human RXRbeta expressed in African green monkey CV1 cells
|
Homo sapiens
|
24.0
nM
|
|
Journal : MedChemComm
Title : Scaffold hopping from synthetic RXR modulators by virtual screening and <i>de novo</i> design.
Year : 2018
Volume : 9
Issue : 8
First Page : 1289
Last Page : 1292
Authors : Merk D, Grisoni F, Friedrich L, Gelzinyte E, Schneider G.
Abstract : The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated <i>de novo</i> design, we identified novel RXR ligands exhibiting innovative molecular frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.
|
Agonist activity at human RXRgamma expressed in African green monkey CV1 cells
|
Homo sapiens
|
25.0
nM
|
|
Journal : MedChemComm
Title : Scaffold hopping from synthetic RXR modulators by virtual screening and <i>de novo</i> design.
Year : 2018
Volume : 9
Issue : 8
First Page : 1289
Last Page : 1292
Authors : Merk D, Grisoni F, Friedrich L, Gelzinyte E, Schneider G.
Abstract : The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated <i>de novo</i> design, we identified novel RXR ligands exhibiting innovative molecular frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-8.87
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Binding affinity to recombinant RXRalpha (unknown origin) by isothermal titration calorimetry
|
Homo sapiens
|
210.0
nM
|
|
Journal : J Med Chem
Title : Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation.
Year : 2019
Volume : 62
Issue : 4
First Page : 2112
Last Page : 2126
Authors : Pollinger J, Gellrich L, Schierle S, Kilu W, Schmidt J, Kalinowsky L, Ohrndorf J, Kaiser A, Heering J, Proschak E, Merk D.
Abstract : The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
|
Agonist activity RXRalpha (unknown origin)
|
Homo sapiens
|
33.0
nM
|
|
Journal : J Med Chem
Title : Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation.
Year : 2019
Volume : 62
Issue : 4
First Page : 2112
Last Page : 2126
Authors : Pollinger J, Gellrich L, Schierle S, Kilu W, Schmidt J, Kalinowsky L, Ohrndorf J, Kaiser A, Heering J, Proschak E, Merk D.
Abstract : The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
|
Agonist activity RXRbeta (unknown origin)
|
Homo sapiens
|
24.0
nM
|
|
Journal : J Med Chem
Title : Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation.
Year : 2019
Volume : 62
Issue : 4
First Page : 2112
Last Page : 2126
Authors : Pollinger J, Gellrich L, Schierle S, Kilu W, Schmidt J, Kalinowsky L, Ohrndorf J, Kaiser A, Heering J, Proschak E, Merk D.
Abstract : The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
|
Agonist activity RXRgamma (unknown origin)
|
Homo sapiens
|
25.0
nM
|
|
Journal : J Med Chem
Title : Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation.
Year : 2019
Volume : 62
Issue : 4
First Page : 2112
Last Page : 2126
Authors : Pollinger J, Gellrich L, Schierle S, Kilu W, Schmidt J, Kalinowsky L, Ohrndorf J, Kaiser A, Heering J, Proschak E, Merk D.
Abstract : The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
|
Agonist activity at human RXRalpha LBD expressed in African green monkey COS1 cells incubated for 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J Med Chem
Title : Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening.
Year : 2019
Volume : 62
Issue : 19
First Page : 8809
Last Page : 8818
Authors : Yamada S, Kawasaki M, Fujihara M, Watanabe M, Takamura Y, Takioku M, Nishioka H, Takeuchi Y, Makishima M, Motoyama T, Ito S, Tokiwa H, Nakano S, Kakuta H.
Abstract : Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
|
Displacement of 9-cis-[11,12-3H]-retinoic acid from human RXRalpha LBD incubated for overnight by scintillation counting method
|
Homo sapiens
|
150.0
nM
|
|
Journal : J Med Chem
Title : Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening.
Year : 2019
Volume : 62
Issue : 19
First Page : 8809
Last Page : 8818
Authors : Yamada S, Kawasaki M, Fujihara M, Watanabe M, Takamura Y, Takioku M, Nishioka H, Takeuchi Y, Makishima M, Motoyama T, Ito S, Tokiwa H, Nakano S, Kakuta H.
Abstract : Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
|
Displacement of CU-6PMN from human RXRalpha LBD incubated for 2 hrs by fluorescence based assay
|
Homo sapiens
|
379.0
nM
|
|
Journal : J Med Chem
Title : Competitive Binding Assay with an Umbelliferone-Based Fluorescent Rexinoid for Retinoid X Receptor Ligand Screening.
Year : 2019
Volume : 62
Issue : 19
First Page : 8809
Last Page : 8818
Authors : Yamada S, Kawasaki M, Fujihara M, Watanabe M, Takamura Y, Takioku M, Nishioka H, Takeuchi Y, Makishima M, Motoyama T, Ito S, Tokiwa H, Nakano S, Kakuta H.
Abstract : Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
|
Agonist activity at human RXR binding domain and activation domain expressed in human HCT116 cells assessed as rexinoid activity incubated for 24 hrs by luciferase reporter gene based mammalian two-hybrid assay
|
Homo sapiens
|
52.0
nM
|
|
Journal : J Med Chem
Title : Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN).
Year : 2016
Volume : 59
Issue : 19
First Page : 8924
Last Page : 8940
Authors : Heck MC, Wagner CE, Shahani PH, MacNeill M, Grozic A, Darwaiz T, Shimabuku M, Deans DG, Robinson NM, Salama SH, Ziller JW, Ma N, van der Vaart A, Marshall PA, Jurutka PW.
Abstract : Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC<sub>50</sub> profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.
|
Inhibition of HDAC1 gene expression in human HUT78 cells at 100 nM incubated for 48 hrs by quantitative real-time PCR method
|
Homo sapiens
|
10.0
%
|
|
Journal : J Med Chem
Title : Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR)-Selective Agonists: Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic Acid (NEt-TMN).
Year : 2016
Volume : 59
Issue : 19
First Page : 8924
Last Page : 8940
Authors : Heck MC, Wagner CE, Shahani PH, MacNeill M, Grozic A, Darwaiz T, Shimabuku M, Deans DG, Robinson NM, Salama SH, Ziller JW, Ma N, van der Vaart A, Marshall PA, Jurutka PW.
Abstract : Sulfonic acid analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene, 1) as well as seven novel and two reported analogues of 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN) were synthesized and assessed for selective retinoid X receptor (RXR) agonism. Compound 1 is FDA-approved for treatment of cutaneous T-cell lymphoma (CTCL); however, 1 can provoke side effects by impacting RXR-dependent receptor pathways. All of the analogues in this study were evaluated for their potential to bind RXR through modeling and then assayed in an RXR-RXR mammalian-2-hybrid (M2H) system and in RXR-responsive element (RXRE)-mediated transcriptional experiments. The EC<sub>50</sub> profiles for these unique analogues and their analogous effectiveness to inhibit proliferation in CTCL cells relative to 1 suggest that these compounds possess similar or even enhanced therapeutic potential. Several compounds also displayed more selective RXR activation with minimal cross-signaling of the retinoic acid receptor. These results suggest that modifications of potent RXR agonists such as NEt-TMN can lead to improved biological selectivity and potency compared with the known therapeutic.
|
Agonist activity at human RXRalpha expressed in African green monkey COS1 cells harboring CRBP2-tk-luc reporter incubated for 18 hrs by steady-glo luciferase reporter gene assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid derivatives as rexinoids with reduced teratogenicity.
Year : 2019
Volume : 29
Issue : 15
First Page : 1891
Last Page : 1894
Authors : Takamura Y, Takahashi M, Nishii M, Shibahara O, Watanabe M, Fujihara M, Kakuta H.
Abstract : Several retinoid X receptor (RXR) ligands (rexinoids), such as bexarotene (1), exhibit teratogenicity, which is a serious impediment to their clinical application. We considered that rexinoids with a lower level of maximal RXR transcription activation (i.e., partial agonists) and lower lipid solubility might show weaker adverse side effects. Based on this idea, we modified our previously reported pentamethyltetralin-type RXR partial agonists 5 and 6 to reduce their lipophilicity. Here, we report a new RXR partial agonist, 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (8, CATF-PMN), which showed greatly reduced teratogenicity in zebrafish embryos.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
32.83
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.83
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.025
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.49
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.49
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.04
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.04
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Binding affinity to human RXRalpha-LBD (224 to 462 residues) expressed in Escherichia coli BL21(DE3) incubated for 1 hr in presence of compound by fluorescence polarization assay
|
Homo sapiens
|
632.0
nM
|
|
Binding affinity to human RXRalpha-LBD (224 to 462 residues) expressed in Escherichia coli BL21(DE3) incubated for 1 hr in presence of compound by fluorescence polarization assay
|
Homo sapiens
|
350.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Creation of Fluorescent RXR Antagonists Based on CBTF-EE and Application to a Fluorescence Polarization Binding Assay.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1024
Last Page : 1029
Authors : Takioku M,Takamura Y,Fujihara M,Watanabe M,Yamada S,Kawasaki M,Ito S,Nakano S,Kakuta H
Abstract : Retinoid X receptor (RXR) ligands often bind in modes in which the carboxy group forms a hydrogen bond inside the ligand-binding pocket (LBP). However, our previously reported RXR antagonist, CBTF-EE (4a), binds with its carboxy group directed outside the LBP and its alkoxy side chain located inside the LBP. Here, we examined the binding modes of 4b and 4c bearing a nitrobenzoxadiazole (NBD) or boron-dipyrromethene (BODIPY) fluorophore, respectively, at the end of the alkoxy chain of 4a. Both compounds function as RXR antagonists. 4c, but not 4b, was available for a fluorescence polarization binding assay, indicating that rotation of BODIPY, but not NBD, is restricted in the bound state. The fluorescence findings, supported by docking simulations, suggest the fluorophores are located outside the LBP, so that the binding mode of 4b and 4c is different from that of 4a. The assay results were highly correlated with those of a [H]9-cis-retinoic acid assay.
|
Binding affinity to human RXRalpha-LBD (224 to 462 residues) expressed in Escherichia coli BL21(DE3) incubated for 1 hr in presence of compound by [3H]9-Cis retinoic acid assay
|
Homo sapiens
|
201.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Creation of Fluorescent RXR Antagonists Based on CBTF-EE and Application to a Fluorescence Polarization Binding Assay.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1024
Last Page : 1029
Authors : Takioku M,Takamura Y,Fujihara M,Watanabe M,Yamada S,Kawasaki M,Ito S,Nakano S,Kakuta H
Abstract : Retinoid X receptor (RXR) ligands often bind in modes in which the carboxy group forms a hydrogen bond inside the ligand-binding pocket (LBP). However, our previously reported RXR antagonist, CBTF-EE (4a), binds with its carboxy group directed outside the LBP and its alkoxy side chain located inside the LBP. Here, we examined the binding modes of 4b and 4c bearing a nitrobenzoxadiazole (NBD) or boron-dipyrromethene (BODIPY) fluorophore, respectively, at the end of the alkoxy chain of 4a. Both compounds function as RXR antagonists. 4c, but not 4b, was available for a fluorescence polarization binding assay, indicating that rotation of BODIPY, but not NBD, is restricted in the bound state. The fluorescence findings, supported by docking simulations, suggest the fluorophores are located outside the LBP, so that the binding mode of 4b and 4c is different from that of 4a. The assay results were highly correlated with those of a [H]9-cis-retinoic acid assay.
