|
Inhibition of [125I]L-T3 binding to rat hepatic 3,5,3''-triiodo-L-thyronine receptor
|
Rattus norvegicus
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of phenoxyphenyl oxamic acid derivatives related to L-thyronine.
Year : 2000
Volume : 10
Issue : 15
First Page : 1661
Last Page : 1663
Authors : Stanton JL, Cahill E, Dotson R, Tan J, Tomaselli HC, Wasvary JM, Stephan ZF, Steele RE.
Abstract : The synthesis of substituted phenoxyphenyl oxamic acid derivatives related to L-thyronine (L-T3) is described. The in vitro and in vivo cholesterol lowering and cardiovascular effects of these compounds are presented and discussed.
|
In vitro inhibition of the bound [125I]L-T3 rat liver nuclear L-triiodothyronine receptor
|
None
|
4.4
nM
|
|
In vitro inhibition of the bound [125I]L-T3 rat liver nuclear L-triiodothyronine receptor
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of oxamic acid and acetic acid derivatives related to L-thyronine.
Year : 1995
Volume : 38
Issue : 4
First Page : 695
Last Page : 707
Authors : Yokoyama N, Walker GN, Main AJ, Stanton JL, Morrissey MM, Boehm C, Engle A, Neubert AD, Wasvary JM, Stephan ZF.
Abstract : Aryloxamic acids 7 and 23, (arylamino)acetic acids 29, arylpropionic acids 33, arylthioacetic acids 37, and (aryloxy)acetic acid 41 related to L-triiodothyronine (L-T3) were prepared and tested in vitro for binding to the rat liver nuclear L-T3 receptor and the rat membrane L-T3 receptor. The structure-activity relationships for these compounds are described, with 7f, 23a, 29c, 33a, 37b, and 41 showing excellent potency (IC50's of 0.19, 0.16, 1.1, 0.11, 3.5, and 0.10 nM, respectively) to the nuclear receptor and significantly lower binding affinity to the membrane receptor (IC50's > 5 microM). Some of these compounds, especially in the oxamic acid series 7 and 23, showed an unprecedented potency for methyl-substituted derivatives such as 7f and 23a. Compounds 7f and 23a showed good lipid lowering effects in rats with ED50's of 20 and 5 micrograms/kg po, respectively, and a lack of cardiac side effects in rats at doses as high as 10 and 25 mg/kg po, respectively.
|
In vitro inhibition of bound [125I]L-T3 rat plasma membrane 3,5,3'' L-triiodothyronine receptor
|
None
|
500.0
nM
|
|
In vitro inhibition of bound [125I]L-T3 rat plasma membrane 3,5,3'' L-triiodothyronine receptor
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of oxamic acid and acetic acid derivatives related to L-thyronine.
Year : 1995
Volume : 38
Issue : 4
First Page : 695
Last Page : 707
Authors : Yokoyama N, Walker GN, Main AJ, Stanton JL, Morrissey MM, Boehm C, Engle A, Neubert AD, Wasvary JM, Stephan ZF.
Abstract : Aryloxamic acids 7 and 23, (arylamino)acetic acids 29, arylpropionic acids 33, arylthioacetic acids 37, and (aryloxy)acetic acid 41 related to L-triiodothyronine (L-T3) were prepared and tested in vitro for binding to the rat liver nuclear L-T3 receptor and the rat membrane L-T3 receptor. The structure-activity relationships for these compounds are described, with 7f, 23a, 29c, 33a, 37b, and 41 showing excellent potency (IC50's of 0.19, 0.16, 1.1, 0.11, 3.5, and 0.10 nM, respectively) to the nuclear receptor and significantly lower binding affinity to the membrane receptor (IC50's > 5 microM). Some of these compounds, especially in the oxamic acid series 7 and 23, showed an unprecedented potency for methyl-substituted derivatives such as 7f and 23a. Compounds 7f and 23a showed good lipid lowering effects in rats with ED50's of 20 and 5 micrograms/kg po, respectively, and a lack of cardiac side effects in rats at doses as high as 10 and 25 mg/kg po, respectively.
|
Binding affinity towards thyroid hormone receptor (hTR alpha 1)
|
Homo sapiens
|
0.17
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A designed antagonist of the thyroid hormone receptor.
Year : 2001
Volume : 11
Issue : 21
First Page : 2821
Last Page : 2825
Authors : Yoshihara HA, Apriletti JW, Baxter JD, Scanlan TS.
Abstract : We synthesized an analogue of the thyromimetic GC-1 bearing the same hydrophobic appendage as the estrogen receptor antagonist ICI-164,384. While having reduced affinity for the thyroid hormone receptors compared to GC-1, it behaves in a manner consistent with a competitive antagonist in a transactivation assay.
|
Effective concentration binding towards TRalpha in E25B2 cells (agonistic activity)
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.
Year : 2003
Volume : 13
Issue : 3
First Page : 379
Last Page : 382
Authors : Dow RL, Schneider SR, Paight ES, Hank RF, Chiang P, Cornelius P, Lee E, Newsome WP, Swick AG, Spitzer J, Hargrove DM, Patterson TA, Pandit J, Chrunyk BA, LeMotte PK, Danley DE, Rosner MH, Ammirati MJ, Simons SP, Schulte GK, Tate BF, DaSilva-Jardine P.
Abstract : In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.
|
Half-maximum activation of human Thyroid hormone receptor alpha-1 (hTRalpha1)
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment.
Year : 2002
Volume : 45
Issue : 15
First Page : 3310
Last Page : 3320
Authors : Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, Scanlan TS.
Abstract : Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.
|
Binding affinity against human Thyroid hormone receptor alpha-1 (hTRalpha1) using radiolabeled T3
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment.
Year : 2002
Volume : 45
Issue : 15
First Page : 3310
Last Page : 3320
Authors : Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, Scanlan TS.
Abstract : Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.
|
Binding affinity of compound was determined against Thyroid hormone receptor alpha1
|
None
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : Structural determinants of selective thyromimetics.
Year : 2003
Volume : 46
Issue : 14
First Page : 3152
Last Page : 3161
Authors : Yoshihara HA, Apriletti JW, Baxter JD, Scanlan TS.
Abstract : The thyromimetic GC-1 shows a preference for binding the beta form of the thyroid hormone receptor (TR). GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an l-alanine polar side chain. The structural features of GC-1 that confer its greater affinity and selectivity compared to DIMIT were analyzed with the preparation of analogues that bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has selectivity comparable to that of GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TR-beta selectivity.
|
Binding affinity towards thyroid hormone receptor (hTR beta 1)
|
Homo sapiens
|
0.14
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A designed antagonist of the thyroid hormone receptor.
Year : 2001
Volume : 11
Issue : 21
First Page : 2821
Last Page : 2825
Authors : Yoshihara HA, Apriletti JW, Baxter JD, Scanlan TS.
Abstract : We synthesized an analogue of the thyromimetic GC-1 bearing the same hydrophobic appendage as the estrogen receptor antagonist ICI-164,384. While having reduced affinity for the thyroid hormone receptors compared to GC-1, it behaves in a manner consistent with a competitive antagonist in a transactivation assay.
|
Effective concentration binding towards TR-beta-1 in E25B2 cells (agonistic activity)
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.
Year : 2003
Volume : 13
Issue : 3
First Page : 379
Last Page : 382
Authors : Dow RL, Schneider SR, Paight ES, Hank RF, Chiang P, Cornelius P, Lee E, Newsome WP, Swick AG, Spitzer J, Hargrove DM, Patterson TA, Pandit J, Chrunyk BA, LeMotte PK, Danley DE, Rosner MH, Ammirati MJ, Simons SP, Schulte GK, Tate BF, DaSilva-Jardine P.
Abstract : In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.
|
Half-maximum activation of human Thyroid hormone receptor beta 1 (hTRbeta1)
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment.
Year : 2002
Volume : 45
Issue : 15
First Page : 3310
Last Page : 3320
Authors : Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, Scanlan TS.
Abstract : Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.
|
Binding affinity against human Thyroid hormone receptor beta 1 (hTRbeta1) using radiolabeled T3
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Rational design and synthesis of a novel thyroid hormone antagonist that blocks coactivator recruitment.
Year : 2002
Volume : 45
Issue : 15
First Page : 3310
Last Page : 3320
Authors : Nguyen NH, Apriletti JW, Cunha Lima ST, Webb P, Baxter JD, Scanlan TS.
Abstract : Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.
|
Binding affinity of compound was determined against thyroid hormone receptor beta 1
|
None
|
0.087
nM
|
|
Journal : J. Med. Chem.
Title : Structural determinants of selective thyromimetics.
Year : 2003
Volume : 46
Issue : 14
First Page : 3152
Last Page : 3161
Authors : Yoshihara HA, Apriletti JW, Baxter JD, Scanlan TS.
Abstract : The thyromimetic GC-1 shows a preference for binding the beta form of the thyroid hormone receptor (TR). GC-1 was designed as an analogue of the thyromimetic DIMIT, which has a lower affinity for TR and is not selective. GC-1 has a methylene group linking its two aromatic rings and an oxyacetic acid polar side chain, while DIMIT has an ether oxygen linking its aromatic rings and an l-alanine polar side chain. The structural features of GC-1 that confer its greater affinity and selectivity compared to DIMIT were analyzed with the preparation of analogues that bear only one of their two different structural features. The analogue of GC-1 with a biaryl ether has selectivity comparable to that of GC-1, while the analogue of DIMIT with a methylene group linking its aromatic rings is only slightly selective. These results demonstrate that the oxyacetic acid side chain of GC-1 is critical in conferring TR-beta selectivity.
|
Inhibitory activity against [125I]T3 binding to human TRbeta1 receptor
|
None
|
0.08
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel series of 6-azauracil-based thyroid hormone receptor ligands: potent, TR beta subtype-selective thyromimetics.
Year : 2003
Volume : 13
Issue : 3
First Page : 379
Last Page : 382
Authors : Dow RL, Schneider SR, Paight ES, Hank RF, Chiang P, Cornelius P, Lee E, Newsome WP, Swick AG, Spitzer J, Hargrove DM, Patterson TA, Pandit J, Chrunyk BA, LeMotte PK, Danley DE, Rosner MH, Ammirati MJ, Simons SP, Schulte GK, Tate BF, DaSilva-Jardine P.
Abstract : In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.
|
In vitro concentration required to displace [125I]L-T3 from rat hepatic nuclei.
|
None
|
1.56
nM
|
|
Journal : J. Med. Chem.
Title : alpha-Methylated analogues of triiodothyroalkanoic acids: synthesis and biological activity.
Year : 1992
Volume : 35
Issue : 3
First Page : 548
Last Page : 552
Authors : Zenker N, Ekpe AE, Hubbard LS.
Abstract : Three novel thyroid hormone analogues: alpha-methyl-3,5,3'-triiodothyroacetic acid, alpha-methyl-3,5,3'-triiodothyropropionic acid, and alpha-methyl-3,5,3',5'-tetraiodothyropropionic acid were synthesized. The hepatic thyroid receptor affinity of these analogues was compared to that other available thyroid analogues. The ability of these compounds to increase the activity of two hepatic enzymes and to lower blood cholesterol was compared to that of L-triiodothyronine. alpha-Methyl-3,5,3'-triiodothyroacetic acid was shown to have less nuclear binding affinity, less enzyme inducing ability, but more blood cholesterol lowering ability than triiodothyroacetic acid. alpha-Methyl-3,5,3',5'-tetraiodothyropropionic acid showed less nuclear binding affinity and less enzyme-inducing activity than alpha-methyl-3,5,3'-triiodothyropropionic acid.
|
Inhibitory concentration against cloned human thyroid hormone receptor beta 1
|
Homo sapiens
|
0.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new class of high affinity thyromimetics containing a phenyl-naphthylene core.
Year : 2005
Volume : 15
Issue : 20
First Page : 4579
Last Page : 4584
Authors : Hangeland JJ, Friends TJ, Doweyko AM, Mellström K, Sandberg J, Grynfarb M, Ryono DE.
Abstract : High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.
|
Inhibitory concentration against cloned human thyroid hormone receptor alpha 1
|
Homo sapiens
|
0.24
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new class of high affinity thyromimetics containing a phenyl-naphthylene core.
Year : 2005
Volume : 15
Issue : 20
First Page : 4579
Last Page : 4584
Authors : Hangeland JJ, Friends TJ, Doweyko AM, Mellström K, Sandberg J, Grynfarb M, Ryono DE.
Abstract : High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.
|
Binding affinity at human thyroid hormone receptor alpha 1 expressed in CHOK1 cells
|
Homo sapiens
|
0.24
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.
Year : 2007
Volume : 17
Issue : 15
First Page : 4131
Last Page : 4134
Authors : Garg N, Li YL, Garcia Collazo AM, Litten C, Ryono DE, Zhang M, Caringal Y, Brigance RP, Meng W, Washburn WN, Agback P, Mellström K, Rehnmark S, Rahimi-Ghadim M, Norin T, Grynfarb M, Sandberg J, Grover G, Malm J.
Abstract : Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
|
Binding affinity at human thyroid hormone receptor beta-1 expressed in CHOK1 cells
|
Homo sapiens
|
0.26
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141.
Year : 2007
Volume : 17
Issue : 15
First Page : 4131
Last Page : 4134
Authors : Garg N, Li YL, Garcia Collazo AM, Litten C, Ryono DE, Zhang M, Caringal Y, Brigance RP, Meng W, Washburn WN, Agback P, Mellström K, Rehnmark S, Rahimi-Ghadim M, Norin T, Grynfarb M, Sandberg J, Grover G, Malm J.
Abstract : Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-alpha-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRbeta(1)-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.
|
Inhibition of human thyroid hormone receptor beta 1
|
Homo sapiens
|
0.257
nM
|
|
Journal : Bioorg. Med. Chem.
Title : QSAR study of selective ligands for the thyroid hormone receptor beta.
Year : 2007
Volume : 15
Issue : 15
First Page : 5251
Last Page : 5261
Authors : Liu H, Gramatica P.
Abstract : In this paper, an accurate and reliable QSAR model of 87 selective ligands for the thyroid hormone receptor beta 1 (TRbeta1) was developed, based on theoretical molecular descriptors to predict the binding affinity of compounds with receptor. The structural characteristics of compounds were described wholly by a large amount of molecular structural descriptors calculated by DRAGON. Six most relevant structural descriptors to the studied activity were selected as the inputs of QSAR model by a robust optimization algorithm Genetic Algorithm. The built model was fully assessed by various validation methods, including internal and external validation, Y-randomization test, chemical applicability domain, and all the validations indicate that the QSAR model we proposed is robust and satisfactory. Thus, the built QSAR model can be used to fast and accurately predict the binding affinity of compounds (in the defined applicability domain) to TRbeta1. At the same time, the model proposed could also identify and provide some insight into what structural features are related to the biological activity of these compounds and provide some instruction for further designing the new selective ligands for TRbeta1 with high activity.
|
Displacement of [125I]T3 from human TRalpha receptor
|
Homo sapiens
|
0.058
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Displacement of [125I]T3 from human TRbeta receptor
|
Homo sapiens
|
0.081
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Effect on human TRalpha transactivation activity in U2OS cells by luciferase reporter assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Effect on human TRbeta transactivation activity in U2OS cells by luciferase reporter assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Effect on human TRalpha transactivation activity in HeLa cells by luciferase reporter assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Effect on human TRbeta transactivation activity in HeLa cells by luciferase reporter assay
|
Homo sapiens
|
2.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of thyroid hormone receptor alpha (TRalpha)-specific analogs with varying inner- and outer-ring substituents.
Year : 2008
Volume : 16
Issue : 2
First Page : 762
Last Page : 770
Authors : Ocasio CA, Scanlan TS.
Abstract : Analogs of the TRalpha-specific thyromimetic CO23 were synthesized and analyzed in vitro using competitive binding and transactivation assays. Like CO23, all analogs bind to both thyroid hormone receptor subtypes with about the same affinity; however, modification of CO23 by derivatization of the 3' position of the outer-ring or replacement of the inner-ring iodides with bromides attenuates binding. Despite lacking a preference in binding to TRalpha, all analogs display TRalpha-specificity in transactivation assays using U2OS and HeLa cells. At best, several agonists exhibit an approximately 6-12-fold preference in transactivation when tested with TRalpha in HeLa cells. One analog, CO24, showed in vivo TRalpha-specific action in a tadpole metamorphosis assay.
|
Activity at androgen receptor ligand binding domain assessed as inhibition of SRC2-3 interaction at 50 uM after 2 hrs by fluorescence polarization assay
|
None
|
24.0
%
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : A surface on the androgen receptor that allosterically regulates coactivator binding.
Year : 2007
Volume : 104
Issue : 41
First Page : 16074
Last Page : 16079
Authors : Estébanez-Perpiñá E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK, Webb P, Fletterick RJ.
Abstract : Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
|
Displacement of [125I]3,5,3'-triiodo-L-thyronine from His-tagged human recombinant TRalpha1 by scintillation proximity assay
|
Homo sapiens
|
0.33
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.
Year : 2008
Volume : 51
Issue : 22
First Page : 7075
Last Page : 7093
Authors : Boyer SH, Jiang H, Jacintho JD, Reddy MV, Li H, Li W, Godwin JL, Schulz WG, Cable EE, Hou J, Wu R, Fujitaki JM, Hecker SJ, Erion MD.
Abstract : Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.
|
Displacement of [125I]3,5,3'-triiodo-L-thyronine His-tagged human recombinant TRbeta1 by scintillation proximity assay
|
Homo sapiens
|
0.68
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs.
Year : 2008
Volume : 51
Issue : 22
First Page : 7075
Last Page : 7093
Authors : Boyer SH, Jiang H, Jacintho JD, Reddy MV, Li H, Li W, Godwin JL, Schulz WG, Cable EE, Hou J, Wu R, Fujitaki JM, Hecker SJ, Erion MD.
Abstract : Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRbeta(1), K(i) < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T(3), PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED(50) 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.
|
Displacement of [125I]T3 from recombinant thyroid hormone receptor alpha expressed in sf9 cells by scintillation proximity assay
|
None
|
0.22
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.
Year : 2007
Volume : 104
Issue : 39
First Page : 15490
Last Page : 15495
Authors : Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL.
Abstract : Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-l-thyronine (T(3)) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.
|
Displacement of [125I]T3 from recombinant thyroid hormone receptor beta expressed in sf9 cells by scintillation proximity assay
|
None
|
0.55
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index.
Year : 2007
Volume : 104
Issue : 39
First Page : 15490
Last Page : 15495
Authors : Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL.
Abstract : Despite efforts spanning four decades, the therapeutic potential of thyroid hormone receptor (TR) agonists as lipid-lowering and anti-obesity agents remains largely unexplored in humans because of dose-limiting cardiac effects and effects on the thyroid hormone axis (THA), muscle metabolism, and bone turnover. TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing TRbeta-mediated suppression of the THA. Herein, we describe a cytochrome P450-activated prodrug of a phosphonate-containing TR agonist that exhibits increased TR activation in the liver relative to extrahepatic tissues and an improved therapeutic index. Pharmacokinetic studies in rats demonstrated that the prodrug (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811) undergoes first-pass hepatic extraction and that cleavage of the prodrug generates the negatively charged TR agonist (3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methylphosphonic acid (MB07344), which distributes poorly into most tissues and is rapidly eliminated in the bile. Enhanced liver targeting was further demonstrated by comparing the effects of MB07811 with 3,5,3'-triiodo-l-thyronine (T(3)) and a non-liver-targeted TR agonist, 3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)phenylacetic acid (KB-141) on the expression of TR agonist-responsive genes in the liver and six extrahepatic tissues. The pharmacologic effects of liver targeting were evident in the normal rat, where MB07811 exhibited increased cardiac sparing, and in the diet-induced obese mouse, where, unlike KB-141, MB07811 reduced cholesterol and both serum and hepatic triglycerides at doses devoid of effects on body weight, glycemia, and the THA. These results indicate that targeting TR agonists to the liver has the potential to lower both cholesterol and triglyceride levels with an acceptable safety profile.
|
Inhibition of rat thyroid hormone receptor
|
Rattus norvegicus
|
0.38
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
DRUGMATRIX: Adenosine A1 radioligand binding (ligand: DPCPX)
|
None
|
410.9
nM
|
|
DRUGMATRIX: Adenosine A1 radioligand binding (ligand: DPCPX)
|
None
|
239.7
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Displacement of [125I]T3 from human recombinant thyroid harmone receptor beta after 16 to 48 hrs by gamma-ray detection
|
Homo sapiens
|
2.29
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia.
Year : 2012
Volume : 20
Issue : 11
First Page : 3622
Last Page : 3634
Authors : Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Nagano R, Matsuzawa A, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K.
Abstract : Thyromimetics that specifically target TRβ have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRβ) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRβ selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.
|
Displacement of [125I]T3 from human recombinant thyroid harmone receptor alpha after 16 to 48 hrs by gamma-ray detection
|
Homo sapiens
|
2.33
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel indane derivatives as liver-selective thyroid hormone receptor β (TRβ) agonists for the treatment of dyslipidemia.
Year : 2012
Volume : 20
Issue : 11
First Page : 3622
Last Page : 3634
Authors : Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Nagano R, Matsuzawa A, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K.
Abstract : Thyromimetics that specifically target TRβ have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRβ) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRβ selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model.
|
Displacement of [125I]-T3 from human TRbeta expressed in insect cells after 16 to 48 hrs by gamma-counting
|
Homo sapiens
|
2.29
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and structure-activity relationship (SAR) of N-[7-(4-hydroxyphenoxy)-6-methylindan-4-yl]malonamic acids as thyroid hormone receptor β (TRβ) selective agonists.
Year : 2013
Volume : 21
Issue : 3
First Page : 592
Last Page : 607
Authors : Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Matsuzawa A, Nagano R, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K.
Abstract : Highly TRβ selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRβ) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRβ selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRβ specificity in a binding assay and exhibited full agonism in a reporter cell assay.
|
Displacement of [125I]-T3 from human TRalpha expressed in insect cells after 16 to 48 hrs by gamma-counting
|
Homo sapiens
|
2.33
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and structure-activity relationship (SAR) of N-[7-(4-hydroxyphenoxy)-6-methylindan-4-yl]malonamic acids as thyroid hormone receptor β (TRβ) selective agonists.
Year : 2013
Volume : 21
Issue : 3
First Page : 592
Last Page : 607
Authors : Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Matsuzawa A, Nagano R, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K.
Abstract : Highly TRβ selective thyromimetics have several potential therapeutic applications. Based on the novel indane derivative KTA-439 with high receptor (TRβ) and organ (liver) selectivity, a series of thyroid hormone analogues were prepared, in which the isopropyl at the 3'-position was replaced with alkyl and aralkyl moieties of variable lengths and branches. Binding assays for these human TRs and reporter cell assays showed that 2-arylethyl derivatives had higher TRβ selectivity than KTA-439. KTA-574, a representative 2-arylethyl derivative, had TRβ specificity in a binding assay and exhibited full agonism in a reporter cell assay.
|
Displacement of [125I]Triiodothyronine from thyroid hormone receptor in Wistar rat liver after 18 hrs
|
Rattus norvegicus
|
0.018
nM
|
|
Displacement of [125I]Triiodothyronine from thyroid hormone receptor in Wistar rat liver after 18 hrs
|
Rattus norvegicus
|
0.034
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [125I]Triiodothyronine from thyroid hormone receptor in Wistar rat liver at 10 uM after 18 hrs relative to control
|
Rattus norvegicus
|
6.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Agonist activity at human recombinant TRbeta1 transfected in CV-1 cells after 8 to 10 hrs by alkaline phosphatase reporter gene assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists.
Year : 2014
Volume : 22
Issue : 1
First Page : 488
Last Page : 498
Authors : Takahashi N, Maeda K, Asano Y, Watanabe N.
Abstract : A series of 1-benzylindole-based TRβ agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.
|
Agonist activity at human recombinant TRalpha1 transfected in CV-1 cells after 8 to 10 hrs by alkaline phosphatase reporter gene assay
|
Homo sapiens
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists.
Year : 2014
Volume : 22
Issue : 1
First Page : 488
Last Page : 498
Authors : Takahashi N, Maeda K, Asano Y, Watanabe N.
Abstract : A series of 1-benzylindole-based TRβ agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.
|
Displacement of [125I]-Triiodothyronine from human recombinant TRbeta1 ligand binding domain after 2 to 3 hrs by beta counting
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists.
Year : 2014
Volume : 22
Issue : 1
First Page : 488
Last Page : 498
Authors : Takahashi N, Maeda K, Asano Y, Watanabe N.
Abstract : A series of 1-benzylindole-based TRβ agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.
|
Displacement of [125I]-Triiodothyronine from human recombinant TRalpha1 ligand binding domain after 2 to 3 hrs by beta counting
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and pharmacological characterization of 1-benzyl-4-aminoindole-based thyroid hormone receptor β agonists.
Year : 2014
Volume : 22
Issue : 1
First Page : 488
Last Page : 498
Authors : Takahashi N, Maeda K, Asano Y, Watanabe N.
Abstract : A series of 1-benzylindole-based TRβ agonists were prepared and evaluated. Compounds 11b' and 11c' were found to have cholesterol-lowering in a rat model with marginal effects on cardiac function and HPT axis. The present work illustrates the potential use of indoles as inner ring isosteres.
|
Agonist activity at recombinant His6-tagged THR-beta (unknown origin) expressed in Escherichia coli BL21(DE3) co-expressing RXR preincubated for 30 mins assessed as biotin-GRIP1 peptide recruitment by HTRF assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia.
Year : 2014
Volume : 57
Issue : 10
First Page : 3912
Last Page : 3923
Authors : Kelly MJ, Pietranico-Cole S, Larigan JD, Haynes NE, Reynolds CH, Scott N, Vermeulen J, Dvorozniak M, Conde-Knape K, Huang KS, So SS, Thakkar K, Qian Y, Banner B, Mennona F, Danzi S, Klein I, Taub R, Tilley J.
Abstract : The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
|
Agonist activity at recombinant His6-tagged THR-alpha (unknown origin) expressed in Escherichia coli BL21(DE3) co-expressing RXR preincubated for 30 mins assessed as biotin-GRIP1 peptide recruitment by HTRF assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor β agonist in clinical trials for the treatment of dyslipidemia.
Year : 2014
Volume : 57
Issue : 10
First Page : 3912
Last Page : 3923
Authors : Kelly MJ, Pietranico-Cole S, Larigan JD, Haynes NE, Reynolds CH, Scott N, Vermeulen J, Dvorozniak M, Conde-Knape K, Huang KS, So SS, Thakkar K, Qian Y, Banner B, Mennona F, Danzi S, Klein I, Taub R, Tilley J.
Abstract : The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
|
Agonist activity at human thyroid hormone receptor alpha expressed in HEK293 cells by luciferase reporter gene assay
|
Homo sapiens
|
0.41
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.
Year : 2014
Volume : 24
Issue : 22
First Page : 5265
Last Page : 5267
Authors : Gege C, Schlüter T, Hoffmann T.
Abstract : Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORβ devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORβ and its biology.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
2.74
%
|
|
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.
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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
|
-0.2
%
|
|
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
|
-0.2
%
|
|
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.
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Binding affinity to recombinant PPARgamma LBD (unknown origin) by isothermal titration calorimetry
|
Homo sapiens
|
710.0
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
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Agonist activity at Xenopus laevis THRalpha transfected in green monkey CV1 cells after 48 hrs by reporter gene assay
|
Xenopus laevis
|
0.5
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at GST-labelled THRbeta ( 202 to 461 residues) (unknown origin) incubated for 2 hrs in presence SRC1-2 co-activator peptide by Alphascreen assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at human THRalpha expressed in CHO cells after 24 hrs by luciferase assay
|
Homo sapiens
|
3.4
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at human THRbeta expressed in CHO cells after 24 hrs by luciferase assay
|
Homo sapiens
|
6.2
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at human THRalpha expressed in baculovirus infected SF9 cells after 15 mins by gel electrophoresis
|
Homo sapiens
|
0.5
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at human THRbeta expressed in green monkey CV1 cells after 24 hrs by luciferase assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Med Chem
Title : l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ.
Year : 2020
Volume : 63
Issue : 13
First Page : 6727
Last Page : 6740
Authors : Gellrich L, Heitel P, Heering J, Kilu W, Pollinger J, Goebel T, Kahnt A, Arifi S, Pogoda W, Paulke A, Steinhilber D, Proschak E, Wurglics M, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Bischoff I, Fürst R, Merk D.
Abstract : Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARγ with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARγ and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARγ and RXR, TETRAC differs markedly in its molecular structure and the PPARγ-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.
|
Agonist activity at recombinant hexa-His-tagged THRalpha LBD (202 to 461 residues) (unknown origin)/recombinant human EE-tagged RXRalpha LBD (225 to 462 residues) assessed as increase in biotinylated GRIP1 peptide recruitment preincubated for 30 mins followed by peptide addition and measured after 30 mins by HTRF assay
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective thyroid hormone receptor β agonists with oxadiazolone acid isosteres.
Year : 2020
Volume : 30
Issue : 21.0
First Page : 127465
Last Page : 127465
Authors : Kirschberg TA,Jones CT,Xu Y,Fenaux M,Halcomb RL,Wang Y,Klucher K
Abstract : Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor β. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.
|
Agonist activity at recombinant hexa-His-tagged THRbeta LBD (148 to 410 residues) (unknown origin)/recombinant human EE-tagged RXRalpha LBD (225 to 462 residues) assessed as increase in biotinylated GRIP1 peptide recruitment preincubated for 30 mins followed by peptide addition and measured after 30 mins by HTRF assay
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective thyroid hormone receptor β agonists with oxadiazolone acid isosteres.
Year : 2020
Volume : 30
Issue : 21.0
First Page : 127465
Last Page : 127465
Authors : Kirschberg TA,Jones CT,Xu Y,Fenaux M,Halcomb RL,Wang Y,Klucher K
Abstract : Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor β. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.
