|
Inhibitory activity against Calcineurin (CaN phosphatase)
|
Rattus norvegicus
|
14.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity.
Year : 1999
Volume : 9
Issue : 14
First Page : 2089
Last Page : 2094
Authors : Armstrong HM, Wong F, Holmes MA, Sinclair PJ, Goulet MT, Dumont FJ, Staruch MJ, Koprak S, Peterson LB, Rosa R, Wilusz MB, Wiederrecht GJ, Cryan JG, Wyvratt MJ, Parsons WH.
Abstract : The synthesis of C32-O-arylethyl ether derivatives of ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.
|
Inhibition of calcineurin phosphatase activity by the compound
|
None
|
11.1
nM
|
|
Journal : J. Med. Chem.
Title : 32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.
Year : 1999
Volume : 42
Issue : 15
First Page : 2798
Last Page : 2804
Authors : Becker JW, Rotonda J, Cryan JG, Martin M, Parsons WH, Sinclair PJ, Wiederrecht G, Wong F.
Abstract : 32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.
|
Binding affinity to protein phosphatase, calcineurin (CN) was determined
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of FK506-Cyclosporin hybrid macrocycles
Year : 1995
Volume : 5
Issue : 20
First Page : 2341
Last Page : 2346
Authors : Teague SJ, Cooper ME, Stocks MJ
|
Compound was tested in vitro for inhibitory activity against human FK506 binding protein
|
Homo sapiens
|
2.54
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies on an immunosuppressive macrolactam, ascomycin: synthesis of a C-33 hydroxyl derivative.
Year : 1998
Volume : 8
Issue : 8
First Page : 935
Last Page : 938
Authors : Kawai M, Gunawardana IW, Mollison KW, Hsieh GC, Lane BC, Luly JR.
Abstract : Ascomycin 2, a close analogue of the immunosuppressant FK506 1, was modified to incorporate a hydroxyl group at the C-33 position. This increased the aqueous solubility of ascomycin by a hundred-fold at pH 7.4 and by approximately 300-fold at pH 6.5. Ascomycin 3 also exhibited an excellent immunosuppressive activity in vitro, as tested in a human mixed lymphocyte proliferation (HuMLR) assay, and in vivo using a rat popliteal lymph node (rPLN) hyperplasia assay.
|
Relative binding affinity of compound for FK506 binding protein (FKBP)
|
None
|
0.39
nM
|
|
Journal : J. Med. Chem.
Title : 32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.
Year : 1999
Volume : 42
Issue : 15
First Page : 2798
Last Page : 2804
Authors : Becker JW, Rotonda J, Cryan JG, Martin M, Parsons WH, Sinclair PJ, Wiederrecht G, Wong F.
Abstract : 32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity of their parent compounds but display reduced toxicity. In addition, their complexes with the 12-kDa FK506-binding protein (FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional structures of the FKBP complexes with two 32-indolyl derivatives of ascomycin. The structures of the protein and the macrolide are remarkably similar to those seen in the complexes with tacrolimus and ascomycin. The indole groups project away from the body of the complex, and multiple conformations are observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Comparison of these structures with that of the ternary complex of calcineurin, FKBP, and tacrolimus suggests that the indole groups interact with a binding site comprising elements of both the calcineurin alpha- and beta-chains and that this interaction is responsible for the increased stability of these complexes.
|
Effective concentration against FK506 binding protein 12 using [3H]-dihydro FK-506
|
Homo sapiens
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity.
Year : 1999
Volume : 9
Issue : 14
First Page : 2089
Last Page : 2094
Authors : Armstrong HM, Wong F, Holmes MA, Sinclair PJ, Goulet MT, Dumont FJ, Staruch MJ, Koprak S, Peterson LB, Rosa R, Wilusz MB, Wiederrecht GJ, Cryan JG, Wyvratt MJ, Parsons WH.
Abstract : The synthesis of C32-O-arylethyl ether derivatives of ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.
|
Inhibitory binding activity against human Immunophilin-FK-506 binding protein 12
|
None
|
2.5
nM
|
|
Journal : J. Med. Chem.
Title : 32-Ascomycinyloxyacetic acid derived immunosuppressants. Independence of immunophilin binding and immunosuppressive potency.
Year : 1998
Volume : 41
Issue : 11
First Page : 1764
Last Page : 1776
Authors : Wagner R, Rhoades TA, Or YS, Lane BC, Hsieh G, Mollison KW, Luly JR.
Abstract : The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.
|
The compound was tested for binding affinity against human FK506 binding protein 12
|
None
|
2.3
nM
|
|
Journal : J. Med. Chem.
Title : Retention of immunosuppressant activity in an ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12.
Year : 1999
Volume : 42
Issue : 21
First Page : 4456
Last Page : 4461
Authors : Wiedeman PE, Fesik SW, Petros AM, Nettesheim DG, Mollison KW, Lane BC, Or YS, Luly JR.
Abstract : C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.
|
Compound was tested for its ability to inhibit FK506 binding protein 12 rotamase activity
|
None
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Immunophilins: beyond immunosuppression.
Year : 1998
Volume : 41
Issue : 26
First Page : 5119
Last Page : 5143
Authors : Hamilton GS, Steiner JP.
|
Binding affinity to FK506 binding protein 12 was determined
|
None
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of FK506-Cyclosporin hybrid macrocycles
Year : 1995
Volume : 5
Issue : 20
First Page : 2341
Last Page : 2346
Authors : Teague SJ, Cooper ME, Stocks MJ
|
The compound was evaluated for its affinity to the binding domain of immunophilin FK506 binding protein 12
|
None
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The affinity of the excised binding domain of FK-506 for the immunophilin FKBP12.
Year : 1993
Volume : 3
Issue : 10
First Page : 1947
Last Page : 1950
Authors : Teague SJ, Stocks MJ
|
The inhibitory activity by using FK506 binding protein 12 SPA binding assay
|
None
|
3.162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Solid-phase/solution-phase combinatorial synthesis of neuroimmunophilin ligands.
Year : 2000
Volume : 10
Issue : 10
First Page : 1007
Last Page : 1010
Authors : Rabinowitz M, Seneci P, Rossi T, Dal Cin M, Deal M, Terstappen G.
Abstract : A novel solid-phase/solution-phase strategy for the synthesis of neuroimmunophilin ligands based on GPI 1046 was developed. The synthesis employs a solid-phase esterification strategy followed by a solution-phase pyruvic amide formation to produce multi-milligram quantities of discrete compounds for assay. The protocol was applied to a production library of 880 discrete compounds. A highlight of the strategy is an aqueous extractive purification of the final compounds using a novel liquid/ice extraction system developed for high throughput.
|
Inhibition of human mixed lymphocyte response (MLR)
|
Homo sapiens
|
0.48
nM
|
|
Journal : J. Med. Chem.
Title : 32-Ascomycinyloxyacetic acid derived immunosuppressants. Independence of immunophilin binding and immunosuppressive potency.
Year : 1998
Volume : 41
Issue : 11
First Page : 1764
Last Page : 1776
Authors : Wagner R, Rhoades TA, Or YS, Lane BC, Hsieh G, Mollison KW, Luly JR.
Abstract : The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.
|
Compound was tested in vitro for inhibition of human mixed lymphocyte proliferation (HuMLR)
|
Homo sapiens
|
0.37
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies on an immunosuppressive macrolactam, ascomycin: synthesis of a C-33 hydroxyl derivative.
Year : 1998
Volume : 8
Issue : 8
First Page : 935
Last Page : 938
Authors : Kawai M, Gunawardana IW, Mollison KW, Hsieh GC, Lane BC, Luly JR.
Abstract : Ascomycin 2, a close analogue of the immunosuppressant FK506 1, was modified to incorporate a hydroxyl group at the C-33 position. This increased the aqueous solubility of ascomycin by a hundred-fold at pH 7.4 and by approximately 300-fold at pH 6.5. Ascomycin 3 also exhibited an excellent immunosuppressive activity in vitro, as tested in a human mixed lymphocyte proliferation (HuMLR) assay, and in vivo using a rat popliteal lymph node (rPLN) hyperplasia assay.
|
The compound was tested for its inhibitory activity against T-cell proliferation using murine splenic T-cells
|
Mus musculus
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Potent immunosuppressive C32-O-arylethyl ether derivatives of ascomycin with reduced toxicity.
Year : 1999
Volume : 9
Issue : 14
First Page : 2089
Last Page : 2094
Authors : Armstrong HM, Wong F, Holmes MA, Sinclair PJ, Goulet MT, Dumont FJ, Staruch MJ, Koprak S, Peterson LB, Rosa R, Wilusz MB, Wiederrecht GJ, Cryan JG, Wyvratt MJ, Parsons WH.
Abstract : The synthesis of C32-O-arylethyl ether derivatives of ascomycin that possess equivalent immunosuppressant activity but reduced toxicity, compared to FK-506, is described.
|
Exogenous inhibition concentration of Serine/threonine protein phosphatase 2B (PP2B)
|
None
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies.
Year : 2002
Volume : 45
Issue : 6
First Page : 1151
Last Page : 1175
Authors : McCluskey A, Sim AT, Sakoff JA.
|
In vitro evaluation for immunosuppressive activity against proliferation of antigen stimulated murine splenic T cells
|
Mus musculus
|
0.29
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkyl ether analogs of the FK-506 related, immunosuppressive macrolide L-683,590 (ascomycin)
Year : 1994
Volume : 4
Issue : 7
First Page : 921
Last Page : 926
Authors : Goulet MT, Hodkey DW, Staruch MJ, Dumont FJ, Cryan JG, Parsons WH, Wyvratt MJ
|
In vitro inhibitory activity against human T-cell production of lymphokine IL-2
|
Homo sapiens
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : The C-32 triacetyl-L-rhamnose derivative of ascomycin: a potent, orally active macrolactone immunosuppressant.
Year : 1995
Volume : 38
Issue : 8
First Page : 1255
Last Page : 1258
Authors : Koch K, Newborg MF, Hanson DC, Cooper K, Shepard RM, Biehl ML, Biggers MS, Ramchandani M, Schulte G, Snyder JR.
|
In vitro inhibitory activity against human T-cell proliferation.
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : The C-32 triacetyl-L-rhamnose derivative of ascomycin: a potent, orally active macrolactone immunosuppressant.
Year : 1995
Volume : 38
Issue : 8
First Page : 1255
Last Page : 1258
Authors : Koch K, Newborg MF, Hanson DC, Cooper K, Shepard RM, Biehl ML, Biggers MS, Ramchandani M, Schulte G, Snyder JR.
|
Agonistic activity in a murine splenic T-cell proliferation assay was calculated by measurement of [3H]thymidine uptake relative to control
|
Mus musculus
|
0.18
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel derivatives at the C21 position of the FK-506 macrocycle
Year : 1993
Volume : 3
Issue : 4
First Page : 657
Last Page : 662
Authors : Organ HM, Holmes MA, Pisano JM, Staruch MJ, Wyvratt MJ, Dumont FJ, Sinclair PJ
|
In vitro immunosuppressive activity against proliferation of antigen stimulated murine splenic T cells
|
Mus musculus
|
0.29
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Alkyl ether derivatives of the FK-506 related, immunosuppressive macrolide L-683,742 (C31-O-desmethyl ascomycin)
Year : 1994
Volume : 4
Issue : 7
First Page : 927
Last Page : 930
Authors : Goulet MT, Hodkey DW, Staruch MJ, Dumont FJ, Lin S, Hung SH, Siekierka JJ, Wyvratt MJ
|
Immunosuppressive activity examined in an in vitro model of allogenic T-lymphocyte activation (by MLR assay)
|
Homo sapiens
|
0.23
nM
|
|
Journal : J. Med. Chem.
Title : Retention of immunosuppressant activity in an ascomycin analogue lacking a hydrogen-bonding interaction with FKBP12.
Year : 1999
Volume : 42
Issue : 21
First Page : 4456
Last Page : 4461
Authors : Wiedeman PE, Fesik SW, Petros AM, Nettesheim DG, Mollison KW, Lane BC, Or YS, Luly JR.
Abstract : C24-Deoxyascomycin was prepared in a two-step process from ascomycin and evaluated for its immunosuppressant activity relative to ascomycin and FK506. An intermediate in the synthetic pathway, Delta(23,24)-dehydroascomycin, was likewise evaluated. Despite lacking the hydrogen-bonding interactions associated with the C24-hydroxyl moiety of ascomycin, C24-deoxyascomycin was found to be equipotent to the parent compound both in its immunosuppressive potency and in its interaction with the immunophilin, FKBP12. Conversely, Delta(23,24)-dehydroascomycin which also lacks the same hydrogen-bonding interactions did not exhibit this potency. NMR studies were conducted on the FKBP12/C24-deoxyascomycin complex in an attempt to understand this phenomenon at the molecular level. The NMR structures of the complexes formed between FKBP12 and ascomcyin or C24-deoxyascomcyin were very similar, suggesting that hydrogen-bonding interactions with the C24 hydroxyl moiety are not important for complex formation.
|
Immunosuppressant-like activity in an in vitro splenocyte mitogenesis assay at concentration up to 10 uM
|
None
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of dual domain FKBP ligands
Year : 1994
Volume : 4
Issue : 2
First Page : 325
Last Page : 328
Authors : Yamashita DS, Oh H, Yen H, Bossard MJ, Brandt M, Levy MA, Newman-Tarr T, Badger A, Luengo JI, Holt DA
|
Inhibitory activity against calcineurin phosphatase
|
Homo sapiens
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against macrophilin (FKBP-12)
|
Homo sapiens
|
0.95
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against murine mixed lymphocyte reaction
|
Mus musculus
|
0.29
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against IL-2 receptor in human T-cell jurkat cell line stimulated by phytohemagglutininin and phorbol myristate acetate
|
Homo sapiens
|
0.19
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against PPD-induced proliferation of human peripheral blood mononuclear cell (HPBMNC)
|
Homo sapiens
|
0.18
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against IL-5 production (Anti-CD3 monoclonal antibody stimulated and cultured CD4 positive cells purified from human peripheral blood mononuclear cell)
|
Homo sapiens
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibitory activity against IFN-gamma production (Anti-CD3 monoclonal antibody stimulated and cultured CD4 positive cells purified from human peripheral blood mononuclear cell)
|
Homo sapiens
|
0.06
nM
|
|
Journal : J. Med. Chem.
Title : A locally active antiinflammatory macrolide (MLD987) for inhalation therapy of asthma.
Year : 2004
Volume : 47
Issue : 20
First Page : 4950
Last Page : 4957
Authors : Hersperger R, Buchheit KH, Cammisuli S, Enz A, Lohse O, Ponelle M, Schuler W, Schweitzer A, Walker C, Zehender H, Zenke G, Zimmerlin AG, Zollinger M, Mazzoni L, Fozard JR.
Abstract : One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.
|
Inhibition of DNP7-BSA antigen-induced TNFalpha release in rat RBL-2H3 cells
|
Rattus norvegicus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Vialinin B, a novel potent inhibitor of TNF-alpha production, isolated from an edible mushroom, Thelephora vialis.
Year : 2006
Volume : 16
Issue : 20
First Page : 5424
Last Page : 5426
Authors : Xie C, Koshino H, Esumi Y, Onose J, Yoshikawa K, Abe N.
Abstract : A novel dibenzofuran compound designated vialinin B was isolated from dry fruiting bodies of an edible mushroom, Thelephora vialis, and potently inhibits TNF-alpha production in RBL-2H3 cells (IC(50)=0.02nM) and is a promising anti-allergic agent.
|
Immunosuppressant activity in mouse T cells assessed as inhibition of concanavalin A-induced cell proliferation
|
Mus musculus
|
1.5e-05
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Immunomodulatory constituents from an Ascomycete, Eupenicillium crustaceum, and revised absolute structure of macrophorin D.
Year : 2001
Volume : 64
Issue : 9
First Page : 1234
Last Page : 1237
Authors : Fujimoto H, Nakamura E, Kim YP, Okuyama E, Ishibashi M, Sassa T.
Abstract : Fractionation guided by immunomodulatory activity of the EtOAc extract of the Ascomycete Eupenicillium crustaceum has afforded two new naturally occurring products, 4'-oxomacrophorin D (1) and 4'-oxomacrophorin A (2), as the immunosuppressive components of this fungus [1: 3-hydroxy-3-methylglutaryl (HMG) conjugate of 2]. The structures including the absolute configurations of 1 and 2 have been determined on the basis of chemical correlation of 1 with macrophorin D (3). The absolute configuration of the HMG moiety in 3 has been revised from 3R to 3S.
|
Immunosuppressant activity in mouse B cells assessed as inhibition of LPS-induced cell proliferation
|
Mus musculus
|
0.0016
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Immunomodulatory constituents from an Ascomycete, Eupenicillium crustaceum, and revised absolute structure of macrophorin D.
Year : 2001
Volume : 64
Issue : 9
First Page : 1234
Last Page : 1237
Authors : Fujimoto H, Nakamura E, Kim YP, Okuyama E, Ishibashi M, Sassa T.
Abstract : Fractionation guided by immunomodulatory activity of the EtOAc extract of the Ascomycete Eupenicillium crustaceum has afforded two new naturally occurring products, 4'-oxomacrophorin D (1) and 4'-oxomacrophorin A (2), as the immunosuppressive components of this fungus [1: 3-hydroxy-3-methylglutaryl (HMG) conjugate of 2]. The structures including the absolute configurations of 1 and 2 have been determined on the basis of chemical correlation of 1 with macrophorin D (3). The absolute configuration of the HMG moiety in 3 has been revised from 3R to 3S.
|
Immunosuppressive activity in BALB/c mouse splenic T lymphocytes assessed as inhibition of Con A-induced cell proliferation after 72 hrs by MTT assay
|
Mus musculus
|
1.5e-05
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Immunomodulatory constituents from an Ascomycete, Chaetomium seminudum.
Year : 2004
Volume : 67
Issue : 1
First Page : 98
Last Page : 102
Authors : Fujimoto H, Sumino M, Okuyama E, Ishibashi M.
Abstract : A screening study focusing on immunomodulatory activity of the EtOAc extract of an Ascomycete, Chaetomium seminudum, has afforded a known epipolythiodioxopiperazine, chetomin (1), together with three new chetomin-related metabolites named chetoseminudins A (2), B (3), and C (4). Among these four metabolites, 1 and 2 have been deduced as the immunosuppressive features of this fungus.
|
Immunosuppressive activity in BALB/c mouse splenic B lymphocytes assessed as inhibition of LPS-induced cell proliferation after 72 hrs by MTT assay
|
Mus musculus
|
0.0016
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Immunomodulatory constituents from an Ascomycete, Chaetomium seminudum.
Year : 2004
Volume : 67
Issue : 1
First Page : 98
Last Page : 102
Authors : Fujimoto H, Sumino M, Okuyama E, Ishibashi M.
Abstract : A screening study focusing on immunomodulatory activity of the EtOAc extract of an Ascomycete, Chaetomium seminudum, has afforded a known epipolythiodioxopiperazine, chetomin (1), together with three new chetomin-related metabolites named chetoseminudins A (2), B (3), and C (4). Among these four metabolites, 1 and 2 have been deduced as the immunosuppressive features of this fungus.
|
Inhibition of SAP130 mediated cell growth in human WiDr cells
|
Homo sapiens
|
10.9
nM
|
|
Journal : Nat. Chem. Biol.
Title : Splicing factor SF3b as a target of the antitumor natural product pladienolide.
Year : 2007
Volume : 3
Issue : 9
First Page : 570
Last Page : 575
Authors : Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M, Ishihama Y, Iwata M, Mizui Y.
Abstract : Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter. Despite the unique mechanisms of action and prominent antitumor activities of pladienolides B and D in diverse in vitro and in vivo systems, their target protein has remained unclear. We used 3H-labeled, fluorescence-tagged and photoaffinity/biotin (PB)-tagged 'chemical probes' to identify a 140-kDa protein in splicing factor SF3b as the binding target of pladienolide. Immunoblotting of an enhanced green fluorescent protein fusion protein of SF3b subunit 3 (SAP130) revealed direct interaction between the PB probe and SAP130. The binding affinities of pladienolide derivatives to the SF3b complex were highly correlated with their inhibitory activities against reporter gene expression and cell proliferation. Furthermore, pladienolide B impaired in vivo splicing in a dose-dependent manner. Our results demonstrate that the SF3b complex is a pharmacologically relevant protein target of pladienolide and suggest that this splicing factor is a potential antitumor drug target.
|
Inhibition of SAP130 in VEGF-stimulated human U251 cells by PLAP reporter gene assay
|
Homo sapiens
|
13.8
nM
|
|
Journal : Nat. Chem. Biol.
Title : Splicing factor SF3b as a target of the antitumor natural product pladienolide.
Year : 2007
Volume : 3
Issue : 9
First Page : 570
Last Page : 575
Authors : Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M, Ishihama Y, Iwata M, Mizui Y.
Abstract : Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter. Despite the unique mechanisms of action and prominent antitumor activities of pladienolides B and D in diverse in vitro and in vivo systems, their target protein has remained unclear. We used 3H-labeled, fluorescence-tagged and photoaffinity/biotin (PB)-tagged 'chemical probes' to identify a 140-kDa protein in splicing factor SF3b as the binding target of pladienolide. Immunoblotting of an enhanced green fluorescent protein fusion protein of SF3b subunit 3 (SAP130) revealed direct interaction between the PB probe and SAP130. The binding affinities of pladienolide derivatives to the SF3b complex were highly correlated with their inhibitory activities against reporter gene expression and cell proliferation. Furthermore, pladienolide B impaired in vivo splicing in a dose-dependent manner. Our results demonstrate that the SF3b complex is a pharmacologically relevant protein target of pladienolide and suggest that this splicing factor is a potential antitumor drug target.
|
Inhibition of mycophenolic acid glucuronidation by human kidney microsomes
|
Homo sapiens
|
33.0
nM
|
|
Journal : Pharmacology and Therapeutics
Title : UDP-glucuronosyltransferases and clinical drug-drug interactions.
Year : 2005
Volume : 106
Issue : 1
First Page : 97
Last Page : 132
Authors : Kiang TK, Ensom MH, Chang TK.
Abstract : UDP-glucuronosyltransferase (UGT) enzymes catalyze the conjugation of various endogenous substances (e.g., bilirubin) and exogenous compounds (e.g., drugs). The human UGT superfamily is comprised of 2 families (UGT1 and UGT2) and 3 subfamilies (UGT1A, UGT2A, and UGT2B). Many of the individual UGT enzymes are expressed not only in liver but also in extrahepatic tissues, where the extent of glucuronidation can be substantial. Several others (e.g., UGT1A7, UGT1A8, and UGT1A10) are expressed only in extrahepatic tissues. The molecular regulation of UGT enzyme is still not fully understood, but various transcription factors appear to play a regulatory role. The expression of individual UGT enzymes is subject to genetic polymorphism and these enzymes can be inhibited or induced by xenobiotics. Experimental evidence in humans indicates that the glucuronidation of acetaminophen, codeine, zidovudine, carbamazepine, lorazepam, and propafenone can influenced by specific interacting drugs. In contrast, the glucuronidation of diflunisal, morphine, naproxen, and temazepam is not affected appreciably by the drugs investigated to date. In general, UGT-mediated human drug interaction studies are difficult to interpret. The factors that complicate the interpretation of this type of drug interaction data are discussed.
|
Antiinflammatory activity in rat RBL2H3 cells assessed as inhibition of DNP-BSA-induced TNF-alpha production preincubated for 15 mins prior DNP-BSA challenge measured after 30 mins by ELISA
|
Rattus norvegicus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of a vialinin A analog with a potent inhibitory activity of TNF-α production and its transformation into a couple of bioprobes.
Year : 2012
Volume : 22
Issue : 7
First Page : 2385
Last Page : 2387
Authors : Ye YQ, Onose J, Abe N, Koshino H, Takahashi S.
Abstract : Vialinin A (1) is an extremely potent inhibitor against tumor necrosis factor (TNF)-α production in rat basophilic leukemia (RBL-2H3) cells. This Letter describes the design and synthesis of its advanced analog, 5',6'-dimethyl-1,1':4'1″-terphenyl-2',3',4,4″-tetraol (2) with a comparable inhibitory activity (IC(50)=0.02 nM) to that of 1. The synthesis involved double Suzuki-Miyaura coupling as a key step, and required only five steps from commercially available 3,4-dimethylphenol. For identification of the target molecule, fluorescent and biotinylated derivatives of 2 were prepared through a 'click' coupling process.
|
Binding affinity to human FKBP51 by competitive fluorescence polarization assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control.
Year : 2013
Volume : 56
Issue : 10
First Page : 3922
Last Page : 3935
Authors : Wang Y, Kirschner A, Fabian AK, Gopalakrishnan R, Kress C, Hoogeland B, Koch U, Kozany C, Bracher A, Hausch F.
Abstract : The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.
|
Inhibition of TNF-alpha production in rat RBL2H3 cells after 16 hrs by ELISA
|
Rattus norvegicus
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Vialinin A is a ubiquitin-specific peptidase inhibitor.
Year : 2013
Volume : 23
Issue : 15
First Page : 4328
Last Page : 4331
Authors : Okada K, Ye YQ, Taniguchi K, Yoshida A, Akiyama T, Yoshioka Y, Onose J, Koshino H, Takahashi S, Yajima A, Abe N, Yajima S.
Abstract : Vialinin A, a small compound isolated from the Chinese mushroom Thelephora vialis, exhibits more effective anti-inflammatory activity than the widely used immunosuppressive drug tacrolimus (FK506). Here, we show that ubiquitin-specific peptidase 5/isopeptidase T (USP5/IsoT) is a target molecule of vialinin A, identified by using a beads-probe method. Vialinin A inhibited the peptidase activity of USP5/IsoT and also inhibited the enzymatic activities of USP4 among deubiquitinating enzymes tested. Although USPs are a member of thiol protease family, vialinin A exhibited no inhibitions for other thiol proteases, such as calpain and cathepsin.
|
Inhibition of calcineurin in human Jurkat cells assessed as inhibition of NFAT-mediated IL-2 production after 8 hrs by beta-lactamase reporter gene assay
|
Homo sapiens
|
0.056
nM
|
|
Journal : MedChemComm
Title : Novel FK506 and FK520 analogues via mutasynthesis: mutasynthon scope and product characteristics
Year : 2013
Volume : 4
Issue : 2
First Page : 324
Last Page : 331
Authors : Moss SJ, Stanley-Smith AE, Schell U, Coates NJ, Foster TA, Gaisser S, Gregory MA, Martin CJ, Nur-e-Alam M, Piraee M, Radzom M, Suthar D, Thexton DG, Warneck TD, Zhang M, Wilkinson B
|
Binding affinity to FKBP12 (unknown origin) by NMR analysis
|
Homo sapiens
|
0.4
nM
|
|
Journal : J. Med. Chem.
Title : Elements and modulation of functional dynamics.
Year : 2014
Volume : 57
Issue : 19
First Page : 7819
Last Page : 7837
Authors : Gibbs AC.
Abstract : The existing structure-function paradigm of drug discovery has been evolving toward the essential incorporation of dynamics data. This new functional dynamics paradigm emphasizes conformational entropy as a driving force of protein function and intermolecular recognition. Conformational dynamics (a proxy of conformational entropy) impacts the degree of protein (dis)order and the constitution of the conformational ensemble, the mechanisms of allostery and drug resistance, and the free energy of ligand binding. Specific protein and ligand conformations facilitate favorable, reciprocal interactions. The number of protein and ligand conformers that exhibit favorable binding interactions will vary from system to system. All binding scenarios can modulate protein dynamics by various levels of enthalpic and entropic contribution, with significant influence on the functional dynamics of the system. Analysis and consideration of resulting changes of activity, signaling, catalysis, and subsequent phenotypic outcome are powerful motivations in the drug design process.
|
Inhibition of human CYP3A5 expressed in supersomes assessed inhibition of 1'-OH midazolam formation by LC-MS method
|
Homo sapiens
|
630.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of human CYP3A5 expressed in supersomes assessed inhibition of 1'-OH midazolam formation preincubated with compound before substrate addition by LC-MS method
|
Homo sapiens
|
140.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of human CYP3A5 expressed in supersomes assessed inhibition of 1'-OH midazolam formation preincubated at 2 uM followed by addition of 20-fold diluted buffer with 20 uM MDZ by LC-MS method in presence of NADPH
|
Homo sapiens
|
52.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of human CYP3A4 expressed in supersomes assessed inhibition of 1'-OH midazolam formation preincubated at 2 uM followed by addition of 20-fold diluted buffer with 20 uM MDZ by LC-MS method in presence of NADPH
|
Homo sapiens
|
42.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of human CYP3A4 expressed in supersomes assessed inhibition of 1'-OH midazolam formation by LC-MS method
|
Homo sapiens
|
620.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of human CYP3A4 expressed in supersomes assessed inhibition of 1'-OH midazolam formation preincubated with compound before substrate addition by LC-MS method
|
Homo sapiens
|
120.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Competitive inhibition of CYP3A in human liver microsomes
|
Homo sapiens
|
360.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of CYP3A-mediated 1'-OH midazolam formation in human liver microsomes after 7.5 mins by LC-MS method
|
Homo sapiens
|
940.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Inhibition of CYP3A-mediated 1'-OH midazolam formation in human liver microsomes preincubated for 15 mins before substrate addition by LC-MS method
|
Homo sapiens
|
740.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Reversible competitive inhibition of CYP3A-mediated 1'-OH midazolam formation in human liver microsomes after 7.5 mins by nonlinear regression study
|
Homo sapiens
|
610.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Cyclosporine A- and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro.
Year : 2012
Volume : 40
Issue : 4
First Page : 655
Last Page : 661
Authors : Amundsen R, Åsberg A, Ohm IK, Christensen H.
Abstract : Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs used in the majority of patients with solid organ transplants, generally in combination with a wide range of drugs. CsA and Tac seem not only to be substrates of CYP3A but have also been described as inhibitors of CYP3A. For CsA, in particular, inhibition of CYP3A has been suggested as the main mechanism of interactions seen clinically with various drugs. The aim of this study was to investigate the inhibitory effect and inhibition characteristics of CsA and Tac on CYP3A4 and CYP3A5 in vitro and to evaluate its clinical relevance. Inhibition by CsA and Tac was studied using midazolam as the probe substrate in coincubation and preincubation investigations using human liver microsomes (HLMs) as well as specific CYP3A4- and CYP3A5-expressing insect microsomes (Supersomes). In vitro-in vivo extrapolations (IVIVEs) were performed to evaluate the clinical relevance of the inhibition. Both CsA and Tac competitively inhibited CYP3A in HLMs, showing inhibition constants (K(i)) of 0.98 and 0.61 μM, respectively. Experiments in Supersomes revealed that Tac inhibited both CYP3A4 and CYP3A5, whereas CsA only inhibited CYP3A4. In contrast to the HLM experiments, studies in Supersomes showed inhibition by Tac to be NADPH- and time-dependent, with a 5-fold reduction in IC(50) after preincubation, supporting a time-dependent inhibition mechanism in recombinant microsomes. By application of HLM data, IVIVE estimated the area under the concentration versus time curve of midazolam to increase by 73 and 27% with CsA and Tac, respectively. The inhibitory effect was predominantly on the intestinal level, whereas hepatic intrinsic clearance seemed unaffected.
|
Antiinflammatory activity in ICR mouse assessed as inhibition of picryl chloride-induced contact hypersensitivity reaction administered topically on left ear after 24 hrs
|
Mus musculus
|
53.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.
Year : 2016
Volume : 26
Issue : 4
First Page : 1292
Last Page : 1295
Authors : Tobe M, Tsuboi K, Hasegawa F, Fujiwara N, Inoue Y, Isobe M, Isobe Y.
Abstract : We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.
|
Binding affinity to FKBP51 (unknown origin) by competitive fluorescence polarization assay
|
Homo sapiens
|
79.0
nM
|
|
Journal : J. Med. Chem.
Title : Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.
Year : 2016
Volume : 59
Issue : 6
First Page : 2410
Last Page : 2422
Authors : Gaali S, Feng X, Hähle A, Sippel C, Bracher A, Hausch F.
Abstract : The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization.
|
Antagonist activity at human FKBP12 measured after 30 mins by fluorescein labelled SLF tracer based fluorescence polarization assay
|
Homo sapiens
|
14.05
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A calcineurin antifungal strategy with analogs of FK506.
Year : 2017
Volume : 27
Issue : 11
First Page : 2465
Last Page : 2471
Authors : Nambu M, Covel JA, Kapoor M, Li X, Moloney MK, Numa MM, Soltow QA, Trzoss M, Webb P, Webb RR, Mutz M.
Abstract : A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
|
Antagonist activity at Aspergillus fumigatus FKBP12 measured after 30 mins by fluorescein labelled SLF tracer based fluorescence polarization assay
|
Aspergillus fumigatus
|
18.45
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A calcineurin antifungal strategy with analogs of FK506.
Year : 2017
Volume : 27
Issue : 11
First Page : 2465
Last Page : 2471
Authors : Nambu M, Covel JA, Kapoor M, Li X, Moloney MK, Numa MM, Soltow QA, Trzoss M, Webb P, Webb RR, Mutz M.
Abstract : A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
|
Immunosuppressive activity in PMA/ionomycin stimulated human Jurkat T cells assessed as suppression of IL2 production pretreated for 15 to 30 mins followed by PMA/ionomycin addition measured after 18 to 20 hrs by ELISA
|
Homo sapiens
|
360.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A calcineurin antifungal strategy with analogs of FK506.
Year : 2017
Volume : 27
Issue : 11
First Page : 2465
Last Page : 2471
Authors : Nambu M, Covel JA, Kapoor M, Li X, Moloney MK, Numa MM, Soltow QA, Trzoss M, Webb P, Webb RR, Mutz M.
Abstract : A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
|
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
|
3.58
%
|
|
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.
|
Immunosuppressive activity against BJ6 mouse CD4-positive T cells assessed as inhibition of CD3/CD28-induced cell proliferation
|
Mus musculus
|
2.7e-05
ug.mL-1
|
|
Journal : J Nat Prod
Title : Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity.
Year : 2019
Volume : 82
Issue : 8
First Page : 2078
Last Page : 2086
Authors : Beom JY, Jung JA, Lee KT, Hwangbo A, Song MC, Lee Y, Lee SJ, Oh JH, Ha SJ, Nam SJ, Cheong E, Bahn YS, Yoon YJ.
Abstract : A reduction in the strong immunosuppressive activity of FK506 (<b>1</b>) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (<b>7</b>) exhibited a >900-fold reduction in the <i>in vitro</i> immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. <b>7</b> exhibited robust synergistic antifungal activity with fluconazole. FK506 (<b>1</b>) is a 23-membered macrolide produced by several <i>Streptomyces</i> species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca<sup>2+</sup>-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as <i>Cryptococcus neoformans</i>, <i>Candida albicans</i>, and <i>Aspergillus fumigatus</i>. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
|
Antifungal activity against Cryptococcus neoformans H99
|
Cryptococcus neoformans
|
0.001
ug.mL-1
|
|
Journal : J Nat Prod
Title : Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity.
Year : 2019
Volume : 82
Issue : 8
First Page : 2078
Last Page : 2086
Authors : Beom JY, Jung JA, Lee KT, Hwangbo A, Song MC, Lee Y, Lee SJ, Oh JH, Ha SJ, Nam SJ, Cheong E, Bahn YS, Yoon YJ.
Abstract : A reduction in the strong immunosuppressive activity of FK506 (<b>1</b>) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (<b>7</b>) exhibited a >900-fold reduction in the <i>in vitro</i> immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. <b>7</b> exhibited robust synergistic antifungal activity with fluconazole. FK506 (<b>1</b>) is a 23-membered macrolide produced by several <i>Streptomyces</i> species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca<sup>2+</sup>-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as <i>Cryptococcus neoformans</i>, <i>Candida albicans</i>, and <i>Aspergillus fumigatus</i>. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
|
Antifungal activity against Candida albicans SC5314
|
Candida albicans
|
0.005
ug.mL-1
|
|
Journal : J Nat Prod
Title : Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity.
Year : 2019
Volume : 82
Issue : 8
First Page : 2078
Last Page : 2086
Authors : Beom JY, Jung JA, Lee KT, Hwangbo A, Song MC, Lee Y, Lee SJ, Oh JH, Ha SJ, Nam SJ, Cheong E, Bahn YS, Yoon YJ.
Abstract : A reduction in the strong immunosuppressive activity of FK506 (<b>1</b>) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (<b>7</b>) exhibited a >900-fold reduction in the <i>in vitro</i> immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. <b>7</b> exhibited robust synergistic antifungal activity with fluconazole. FK506 (<b>1</b>) is a 23-membered macrolide produced by several <i>Streptomyces</i> species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca<sup>2+</sup>-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as <i>Cryptococcus neoformans</i>, <i>Candida albicans</i>, and <i>Aspergillus fumigatus</i>. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
|
Antifungal activity against Aspergillus fumigatus Af293
|
Aspergillus fumigatus
|
0.015
ug.mL-1
|
|
Journal : J Nat Prod
Title : Biosynthesis of Nonimmunosuppressive FK506 Analogues with Antifungal Activity.
Year : 2019
Volume : 82
Issue : 8
First Page : 2078
Last Page : 2086
Authors : Beom JY, Jung JA, Lee KT, Hwangbo A, Song MC, Lee Y, Lee SJ, Oh JH, Ha SJ, Nam SJ, Cheong E, Bahn YS, Yoon YJ.
Abstract : A reduction in the strong immunosuppressive activity of FK506 (<b>1</b>) is essential for developing this compound as an antifungal agent. Seven new FK506 analogues modified at both the FK506-binding protein 12- and the calcineurin-binding regions were biosynthesized. 9-DeoxoFK520 (<b>7</b>) exhibited a >900-fold reduction in the <i>in vitro</i> immunosuppressive activity but maintained significant antifungal activity, indicating that the C-9 and C-21 positions are critical for separation of immunosuppressive and antifungal activities. <b>7</b> exhibited robust synergistic antifungal activity with fluconazole. FK506 (<b>1</b>) is a 23-membered macrolide produced by several <i>Streptomyces</i> species and is used as an immunosuppressive drug to prevent the rejection of transplanted organs. FK506 has also exhibited antifungal, neuroprotective, and neuroregenerative activities. In humans, FK506 binds to FK506-binding protein (FKBP) 12, and the resulting FKBP12-FK506 complex interacts with a Ca<sup>2+</sup>-calmodulin-dependent phosphatase, calcineurin (CaN). Inactivation of CaN by forming the FKBP12-FK506-CaN ternary complex prevents the activation of nuclear factor of activated T cells (NF-AT), inhibiting the production of interleukin-2 and subsequent T-cell proliferation. This CaN signaling pathway also plays a critical role in the growth and pathogenesis of major fungal pathogens such as <i>Cryptococcus neoformans</i>, <i>Candida albicans</i>, and <i>Aspergillus fumigatus</i>. Therefore, the synthesis of FK506 analogues that can discriminate human FKBP12/CaN from its fungal counterparts may separate antifungal activity from the immunosuppressive activity, thereby allowing the development of a novel antifungal agent.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.536
%
|
|
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
|
0.02
%
|
|
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
|
0.02
%
|
|
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.
|
Immunosuppressive activity in BALB/C mouse Splenocyte assessed as inhibition of Con A induced cell proliferation at 512 nM after 72 hrs by FACS assay relative to control
|
Mus musculus
|
83.0
%
|
|
Journal : J Nat Prod
Title : Discovery of an Oxepine-Containing Diketopiperazine Derivative Active against Concanavalin A-Induced Hepatitis.
Year : 2020
Volume : 83
Issue : 9.0
First Page : 2672
Last Page : 2678
Authors : Qi C,Tan X,Shi Z,Feng H,Sun L,Hu Z,Chen G,Zhang Y
Abstract : Varioxepine B (1), an oxepine-containing diketopiperazine derivative, was isolated from a marine-derived Aspergillus terreus strain. The structure of 1 was identified by spectroscopic experiments, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. It is noteworthy that 1 could suppressed murine splenocyte proliferation activated by concanavalin A (Con A) in vitro. More importantly, in Con A-challenged mice, pretreatment with 1 obviously decreased the generation of proinflammatory cytokines and ameliorated liver injury. Meanwhile, 1 also exhibited inhibitory activity in anti-CD3/anti-CD28 monoclonal antibodies (mAbs)-induced murine splenocytes and human T cell proliferation as well as both Th1 and Th2 cytokine production.
|
Inhibition of calcineurin phosphatase activity in human Jurkat cells by Western blot analysis
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Antifungal polybrominated proxyphylline derivative induces Candida albicans calcineurin stress response in Galleria mellonella.
Year : 2020
Volume : 30
Issue : 23.0
First Page : 127545
Last Page : 127545
Authors : Gizińska M,Staniszewska A,Kazek M,Koronkiewicz M,Kuryk Ł,Milner-Krawczyk M,Baran J,Borowiecki P,Staniszewska M
Abstract : Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A (CNA) and calcineurin B (CNB) complexes, respectively. PB-WUT-01 acting as a calcineurin inhibitor in the C. albicans cells enhances the cells' susceptibility. Therefore it could be a suitable alternative treatment in patients with candidiasis.
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Inhibition of calcineurin phosphatase activity (unknown origin)
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Homo sapiens
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0.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Antifungal polybrominated proxyphylline derivative induces Candida albicans calcineurin stress response in Galleria mellonella.
Year : 2020
Volume : 30
Issue : 23.0
First Page : 127545
Last Page : 127545
Authors : Gizińska M,Staniszewska A,Kazek M,Koronkiewicz M,Kuryk Ł,Milner-Krawczyk M,Baran J,Borowiecki P,Staniszewska M
Abstract : Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A (CNA) and calcineurin B (CNB) complexes, respectively. PB-WUT-01 acting as a calcineurin inhibitor in the C. albicans cells enhances the cells' susceptibility. Therefore it could be a suitable alternative treatment in patients with candidiasis.
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Immunosuppressive activity in C57BL/6J mouse CD4+ve T cells assessed as inhibition of CD3/CD28-stimulated CD4+ve T cell proliferation incubated for 72 hrs by CellTrace-violet staining based flow cytometry analysis
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Mus musculus
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0.034
nM
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