|
In vitro activation of human peroxisome proliferator activated receptor gamma (PPAR gamma)
|
None
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of novel PPARalpha/gamma/delta triple activators using a known PPARalpha/gamma dual activator as structural template.
Year : 2003
Volume : 13
Issue : 2
First Page : 257
Last Page : 260
Authors : Mogensen JP, Jeppesen L, Bury PS, Pettersson I, Fleckner J, Nehlin J, Frederiksen KS, Albrektsen T, Din N, Mortensen SB, Svensson LA, Wassermann K, Wulff EM, Ynddal L, Sauerberg P.
Abstract : Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR evaluations led to the identification of triple PPARalpha/gamma/delta activators (18-20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARalpha/gamma/delta activation.
|
Inhibition of triglyceride level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
77.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of cholesterol level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
30.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of HDL level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
33.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of glucose level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
33.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of glycerol level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
52.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of free fatty acids level in Syrian golden hamster at 300 umol/kg after 10 days
|
Mesocricetus auratus
|
53.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
Year : 2008
Volume : 16
Issue : 5
First Page : 2489
Last Page : 2498
Authors : Chaturvedi D, Ray S, Srivastava AK, Chander R.
Abstract : omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.
|
Inhibition of synthetic amyloid beta-42 fibrillation by ThT fluorescence analysis relative to control
|
None
|
0.9
%
|
|
Journal : J. Biol. Chem.
Title : Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct.
Year : 2007
Volume : 282
Issue : 14
First Page : 10311
Last Page : 10324
Authors : Necula M, Kayed R, Milton S, Glabe CG.
Abstract : Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
0.2
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Displacement of 1-anilinonaphthalene-8-sulphonic acid from rat recombinant L-FABP high binding affinity site expressed in Escherichia coli BL21 by competitive fluorescence displacement assay
|
Rattus norvegicus
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of the drug binding specificity of rat liver fatty acid binding protein.
Year : 2008
Volume : 51
Issue : 13
First Page : 3755
Last Page : 3764
Authors : Chuang S, Velkov T, Horne J, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an analogous function during the absorption of lipophilic drugs. Binding affinity for L-FABP was assessed by displacement of a fluorescent marker, 1-anilinonaphthalene-8-sulfonic acid (ANS), and the binding site location was determined via nuclear magnetic resonance chemical shift perturbation studies. It was found that the majority of drugs bound to L-FABP at two sites, with the internal site generally having a higher affinity for the compounds tested. Furthermore, in contrast to the interaction of L-FABP with fatty acids, it was demonstrated that a terminal carboxylate is not required for specific binding of lipophilic drugs at the internal site of L-FABP.
|
Displacement of 1-anilinonaphthalene-8-sulphonic acid from rat recombinant L-FABP low binding affinity site expressed in Escherichia coli BL21 by competitive fluorescence displacement assay
|
Rattus norvegicus
|
405.0
nM
|
|
Journal : J. Med. Chem.
Title : Characterization of the drug binding specificity of rat liver fatty acid binding protein.
Year : 2008
Volume : 51
Issue : 13
First Page : 3755
Last Page : 3764
Authors : Chuang S, Velkov T, Horne J, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in the cytosolic solubilization of fatty acids during fat absorption. In the current studies, the interaction of L-FABP with a range of lipophilic drugs has been evaluated to explore the potential for L-FABP to provide an analogous function during the absorption of lipophilic drugs. Binding affinity for L-FABP was assessed by displacement of a fluorescent marker, 1-anilinonaphthalene-8-sulfonic acid (ANS), and the binding site location was determined via nuclear magnetic resonance chemical shift perturbation studies. It was found that the majority of drugs bound to L-FABP at two sites, with the internal site generally having a higher affinity for the compounds tested. Furthermore, in contrast to the interaction of L-FABP with fatty acids, it was demonstrated that a terminal carboxylate is not required for specific binding of lipophilic drugs at the internal site of L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 5 deg C by fluorimetric assay
|
Rattus norvegicus
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 5 deg C by fluorimetric assay
|
Rattus norvegicus
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 42 deg C by fluorimetric assay
|
Rattus norvegicus
|
360.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 37 deg C by fluorimetric assay
|
Rattus norvegicus
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 37 deg C by fluorimetric assay
|
Rattus norvegicus
|
62.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 30 deg C by fluorimetric assay
|
Rattus norvegicus
|
270.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 30 deg C by fluorimetric assay
|
Rattus norvegicus
|
41.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 25 deg C by fluorimetric assay
|
Rattus norvegicus
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 25 deg C by fluorimetric assay
|
Rattus norvegicus
|
32.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 20 deg C by fluorimetric assay
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 20 deg C by fluorimetric assay
|
Rattus norvegicus
|
27.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 15 deg C by fluorimetric assay
|
Rattus norvegicus
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 15 deg C by fluorimetric assay
|
Rattus norvegicus
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP high affinity site expressed in Escherichia coli BL21(DE3) at 10 deg C by fluorimetric assay
|
Rattus norvegicus
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Binding affinity to rat recombinant L-FABP low affinity site expressed in Escherichia coli BL21(DE3) at 10 deg C by fluorimetric assay
|
Rattus norvegicus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Probing the fibrate binding specificity of rat liver fatty acid binding protein.
Year : 2009
Volume : 52
Issue : 17
First Page : 5344
Last Page : 5355
Authors : Chuang S, Velkov T, Horne J, Wielens J, Chalmers DK, Porter CJ, Scanlon MJ.
Abstract : Liver-fatty acid binding protein (L-FABP) is found in high levels in enterocytes and is involved in cytosolic solubilization of fatty acids. In addition, L-FABP has been shown to bind endogenous and exogenous lipophilic compounds, suggesting that it may also play a role in modulating their absorption and disposition within enterocytes. Previously, we have described binding of L-FABP to a range of drugs, including a series of fibrates. In the present study, we have generated structural models of L-FABP-fibrate complexes and undertaken thermodynamic analysis of the binding of fibrates containing either a carboxylic acid or ester functionality. Analysis of the current data reveals that both the location and the energetics of binding are different for fibrates that contain a carboxylate compared to those that do not. As such, the data presented in this study suggest potential mechanisms that underpin molecular recognition and dictate specificity in the interaction between fibrates and L-FABP.
|
Inhibition of human FAAH at 1 uM
|
Homo sapiens
|
-12.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mining biologically-active molecules for inhibitors of fatty acid amide hydrolase (FAAH): identification of phenmedipham and amperozide as FAAH inhibitors.
Year : 2009
Volume : 19
Issue : 23
First Page : 6793
Last Page : 6796
Authors : Vincent F, Nguyen MT, Emerling DE, Kelly MG, Duncton MA.
Abstract : The screening of known medicinal agents against new biological targets has been shown to be a valuable approach for revealing new pharmacology of marketed compounds. Recently, carbamate, urea and ketone inhibitors of fatty acid amide hydrolase (FAAH) have been described as promising treatments for pain, anxiety, depression and other CNS-related conditions. In order to find novel FAAH inhibitors, a focused screen of molecules containing potentially reactive moieties or having in vivo effects that are possibly relevant to the biology of FAAH was conducted. These studies revealed phenmedipham 13 and amperozide 14 to be inhibitors of human FAAH, with an IC(50) of 377 nM and 1.34 microM, respectively.
|
DRUGMATRIX: Serotonin (5-Hydroxytryptamine) 5-HT2A radioligand binding (ligand: [3H] Ketanserin)
|
None
|
605.0
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
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
5.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-10.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
34.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
82.56
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
90.21
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of total cholesterol level in serum at 100 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control
|
Rattus norvegicus
|
35.0
%
|
|
Journal : MedChemComm
Year : 2016
Volume : 7
Issue : 9
First Page : 1858
Last Page : 1869
|
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of phospholipid level in serum at 100 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control
|
Rattus norvegicus
|
37.0
%
|
|
Journal : MedChemComm
Year : 2016
Volume : 7
Issue : 9
First Page : 1858
Last Page : 1869
|
Antihyperlipidemic activity in triton WR-1339 induced Charles Foster rat hyperlipidemia model assessed as inhibition of triglyceride level in serum at 100 mg/kg, po administered simultaneously with triton WR-1339 after 18 hrs by enzymatic method relative to control
|
Rattus norvegicus
|
35.0
%
|
|
Journal : MedChemComm
Year : 2016
Volume : 7
Issue : 9
First Page : 1858
Last Page : 1869
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
7.76
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.44
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
13.99
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
12.37
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
15.83
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
1.23
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-1.95
%
|
|
|
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
|
9.91
%
|
|
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.
|
Antihyperlipidemic activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in serum triglyceride level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
19.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Antihyperlipidemic activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in total cholesterol level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
1.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Antihyperlipidemic activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in atherosclerosis index at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
25.7
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Antihyperlipidemic activity in high fat diet-induced hyperlipidemic mouse model assessed as LDL level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
15.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Antioxidant activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in MDA level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
8.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
In vivo anti-inflammatory activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in TNF-alpha level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
24.6
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
In vivo anti-inflammatory activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in IL-6 level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
16.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Hepatoprotective activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in AST level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
26.7
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
Hepatoprotective activity in high fat diet-induced hyperlipidemic mouse model assessed as reduction in ALT level at 13 mg/kg, po administered for last 30 days during 60 days of high fat diet feeding relative to control
|
Mus musculus
|
10.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3787
Last Page : 3792
Authors : Chen ZZ, Xie YD, Shao LH, Wang QT, Xu YH, Bian XL.
Abstract : Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.79
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.672
%
|
|
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
|
-0.17
%
|
|
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
|
-0.07
%
|
|
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
|
-0.17
%
|
|
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
|
-0.07
%
|
|
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.
