Inhibition of CYP450-mediated tangeretin demethylation in Aspergillus niger ATCC 9142 assessed as relative activity at 0.5 mM
|
Aspergillus niger
|
40.0
%
|
|
Journal : J. Nat. Prod.
Title : Biotransformation of polymethoxylated flavonoids: access to their 4'-O-demethylated metabolites.
Year : 2007
Volume : 70
Issue : 6
First Page : 1035
Last Page : 1038
Authors : Buisson D, Quintin J, Lewin G.
Abstract : Regioselective O-demethylation of the flavones tangeretin (1) and 3-hydroxytangeretin (6) into their 4'-O-demethylated metabolites was performed by using an Aspergillus niger strain. This method serves as a straightforward alternative to multistep synthesis or semisynthesis. The microbial approach is complementary to the chemical procedure, which furnishes a 5-O-demethylated product. P450 inhibitors prevented the biotransformation of tangeretin (1). These results suggest that a P450 oxidation system might be involved in this O-demethylation and demonstrate a consequent similarity in both microbial and mammalian metabolism of polymethoxylated flavones.
Displacement of [131I]IMTO from CYP450c 11 in Wistar rat adrenal membrane
|
Rattus norvegicus
|
1.16
nM
|
|
Journal : J. Med. Chem.
Title : New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues.
Year : 2008
Volume : 51
Issue : 7
First Page : 2244
Last Page : 2253
Authors : Zolle IM, Berger ML, Hammerschmidt F, Hahner S, Schirbel A, Peric-Simov B.
Abstract : Derivatives of etomidate were evaluated as inhibitors of adrenal steroid 11beta-hydroxylations. Stereoselective coupling by Mitsunobu produced chirally pure analogues to study the effect of configuration, modification of the ester, and substitution in the phenyl ring, with the aim to probe specific sites for introducing a radionuclide. Iodophenyl metomidate (IMTO) labeled with iodine-131 served as radioligand for structure-affinity relationship studies. We have characterized the kinetic parameters of specific (131)I-IMTO binding on rat adrenal membranes and used the displacement of (131)I-IMTO binding to evaluate functionalized MTO analogues. Our results indicated that (1) ( R)-configuration is essential for high affinity, (2) highest potency resides in the ethyl, 2-propyl, and 2-fluoroethyl esters, and (3) substitution of the phenyl ring is well tolerated. The clinically used inhibitors metyrapone and ketoconazole inhibited (131)I-IMTO binding with low affinity. Incubation of selected analogues with human adrenocortical NCI-h295 cells demonstrated a high correlation with the inhibitory effect on cortisol secretion.
Inhibition of human aldosterone synthase expressed in chinese hamster V79 cells at 500 nM using 11-deoxycorticosterone as substrate
|
Homo sapiens
|
79.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human steroid-11beta-hydroxylase expressed in chinese hamster V79 cells at 500 nM using 11-deoxycorticosterone as substrate
|
Homo sapiens
|
94.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human aldosterone synthase expressed in chinese hamster V79 cells using 11-deoxycorticosterone as substrate
|
Homo sapiens
|
72.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human steroid-11beta-hydroxylase expressed in chinese hamster V79 cells using 11-deoxycorticosterone as substrate
|
Homo sapiens
|
14.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human CYP17 expressed in Escherichia coli at 2000 nM using progesterone as substrate
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human placental CYP19 at 500 nM using androstenedione as substrate
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2).
Year : 2011
Volume : 21
Issue : 1
First Page : 186
Last Page : 190
Authors : Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA.
Abstract : A series of 23 N-(Pyridin-3-yl)benzamides was synthesized and evaluated for their potential to inhibit human steroid-11β-hydroxylase (CYP11B1) and human aldosterone synthase (CYP11B2). The most potent and selective CYP11B2 inhibitors (IC(50) values 53-166 nM) were further evaluated for their potential to inhibit human CYP17 and CYP19, and no inhibition was observed. Clear evidence was shown for N-(Pyridin-3-yl)benzamides to be a highly selective class of CYP11B2 inhibitors in vitro.
Inhibition of human CYP11B1 expressed in hamster V79MZ cells using 11-deoxycorticosterone substrate
|
Homo sapiens
|
15.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases.
Year : 2011
Volume : 2
Issue : 1
First Page : 2
Last Page : 6
Authors : Hille UE, Zimmer C, Vock CA, Hartmann RW.
Abstract : Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors of CYP11B1, the key enzyme of cortisol biosynthesis, as potential drugs for the treatment of Cushing's syndrome and related diseases. Thus, compound 33 (IC50 = 152 nM) is the first CYP11B1 inhibitor showing a rather good selectivity toward the most important steroidogenic CYP enzymes aldosterone synthase (CYP11B2), the androgen-forming CYP17, and aromatase (estrogen synthase, CYP19).
Inhibition of human CYP11B2 expressed in hamster V79MZ cells using 11-deoxycorticosterone substrate
|
Homo sapiens
|
72.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases.
Year : 2011
Volume : 2
Issue : 1
First Page : 2
Last Page : 6
Authors : Hille UE, Zimmer C, Vock CA, Hartmann RW.
Abstract : Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors of CYP11B1, the key enzyme of cortisol biosynthesis, as potential drugs for the treatment of Cushing's syndrome and related diseases. Thus, compound 33 (IC50 = 152 nM) is the first CYP11B1 inhibitor showing a rather good selectivity toward the most important steroidogenic CYP enzymes aldosterone synthase (CYP11B2), the androgen-forming CYP17, and aromatase (estrogen synthase, CYP19).
DRUGMATRIX: CYP450, 3A4 enzyme inhibition (substrate: 7-Benzyloxy-4-(trifluoromethyl)-coumarin)
|
None
|
800.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
Inhibition of human CYP11B1 expressed in hamster V79 MZ cells using [3H] 11 deoxycorticosterone as substrate by HPLC radioflow detector
|
Homo sapiens
|
15.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Optimization of the First Selective Steroid-11β-hydroxylase (CYP11B1) Inhibitors for the Treatment of Cortisol Dependent Diseases.
Year : 2011
Volume : 2
Issue : 8
First Page : 559
Last Page : 564
Authors : Hille UE, Zimmer C, Haupenthal J, Hartmann RW.
Abstract : CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels, such as Cushing's syndrome or metabolic disease. Expanding on a previous study from our group resulting in the first potent and rather selective inhibitor described so far (1, IC50 = 152 nM), we herein describe further optimizations of the imidazolylmethyl pyridine core. Five compounds among the 42 substances synthesized showed IC50 values below 50 nM. Most interesting was the naphth-1-yl compound 23 (IC50 = 42 nM), showing a 49-fold selectivity toward the highly homologous CYP11B2 (1: 18-fold) as well as selectivity toward the androgen and estrogen forming enzymes CYP17 and CYP19, respectively.
Inhibition of human CYP11B2 expressed in hamster V79 MZ cells using [3H] 11 deoxycorticosterone as substrate by HPLC radioflow detector
|
Homo sapiens
|
72.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Optimization of the First Selective Steroid-11β-hydroxylase (CYP11B1) Inhibitors for the Treatment of Cortisol Dependent Diseases.
Year : 2011
Volume : 2
Issue : 8
First Page : 559
Last Page : 564
Authors : Hille UE, Zimmer C, Haupenthal J, Hartmann RW.
Abstract : CYP11B1 is the key enzyme in cortisol biosynthesis, and its inhibition with selective compounds is a promising strategy for the treatment of diseases associated with elevated cortisol levels, such as Cushing's syndrome or metabolic disease. Expanding on a previous study from our group resulting in the first potent and rather selective inhibitor described so far (1, IC50 = 152 nM), we herein describe further optimizations of the imidazolylmethyl pyridine core. Five compounds among the 42 substances synthesized showed IC50 values below 50 nM. Most interesting was the naphth-1-yl compound 23 (IC50 = 42 nM), showing a 49-fold selectivity toward the highly homologous CYP11B2 (1: 18-fold) as well as selectivity toward the androgen and estrogen forming enzymes CYP17 and CYP19, respectively.
Inhibition of microsomal CYP19 in human placenta using [1beta-3H]-androstenedione as substrate at 2 uM by 3H2O method relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Cushing's syndrome: development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type.
Year : 2013
Volume : 56
Issue : 15
First Page : 6022
Last Page : 6032
Authors : Emmerich J, Hu Q, Hanke N, Hartmann RW.
Abstract : Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.
Inhibition of human CYP17 expressed in Escherichia coli co-expressing rat NADPH-P450 reductase using progesterone as substrate at 2 uM relative to control
|
Homo sapiens
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Cushing's syndrome: development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type.
Year : 2013
Volume : 56
Issue : 15
First Page : 6022
Last Page : 6032
Authors : Emmerich J, Hu Q, Hanke N, Hartmann RW.
Abstract : Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.
Inhibition of human CYP11B2 expressed in hamster V79MZh cells using [1,2-3H]-11-deoxycorticosterone as substrate
|
Homo sapiens
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Cushing's syndrome: development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type.
Year : 2013
Volume : 56
Issue : 15
First Page : 6022
Last Page : 6032
Authors : Emmerich J, Hu Q, Hanke N, Hartmann RW.
Abstract : Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.
Inhibition of human CYP11B1 expressed in hamster V79MZh cells using [1,2-3H]-11-deoxycorticosterone as substrate
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Cushing's syndrome: development of highly potent and selective CYP11B1 inhibitors of the (pyridylmethyl)pyridine type.
Year : 2013
Volume : 56
Issue : 15
First Page : 6022
Last Page : 6032
Authors : Emmerich J, Hu Q, Hanke N, Hartmann RW.
Abstract : Potent and selective CYP11B1 inhibitors could be promising therapeutics for the treatment of Cushing's syndrome. Optimization of Ref 1 (5-((1H-imidazol-1-yl)methyl)-2-phenylpyridine) led to compound 44 (5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine) with a 50-fold improved IC50 value of 2 nM toward human CYP11B1 and an enhanced inhibition of the rat enzyme (IC50 = 2440 nM) compared to Ref 1 (IC50 > 10000 nM). Furthermore, selectivities over CYP11B2, CYP17, and CYP19 were observed, as well as satisfying metabolic stability not only in human and rat plasma but also in liver S9 fraction. Investigation of cytotoxicity and inhibition of hepatic CYP2A6 and CYP3A4 showed that 44 fulfills first safety criteria and can be considered for further in vivo evaluation in rats.
Inhibition of CYP11B1 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate at 500 nM preincubated for 60 mins followed by substrate addition measured after 25 mins by HPLC analysis relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of CYP11B1 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate preincubated for 60 mins followed by substrate addition measured after 25 mins by HPLC analysis
|
Homo sapiens
|
14.6
nM
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of CYP11B2 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate at 500 nM preincubated for 60 mins followed by substrate addition measured after 50 mins by HPLC analysis relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of CYP11B2 (unknown origin) expressed in Chinese hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate preincubated for 60 mins followed by substrate addition measured after 50 mins by HPLC analysis
|
Homo sapiens
|
71.8
nM
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of human CYP17 expressed in Escherichia coli using progesterone as substrate at 2 uM preincubated for 5 mins followed by enzyme addition measured after 30 mins by HPLC analysis relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of CYP19 isolated from microsomal fraction of human term placental tissue using [1beta-3H] androstenedione as substrate at 2 uM preincubated for 5 mins followed by enzyme addition measured after 20 mins by beta scintillation counting analysis relative to control
|
Homo sapiens
|
0.0
%
|
|
Journal : MedChemComm
Title : Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors
Year : 2012
Volume : 3
Issue : 6
First Page : 663
Last Page : 666
Authors : Abadi AH, Abou-Seri SM, Hu Q, Negri M, Hartmann RW
Inhibition of bovine adrenal gland 11beta-hydroxylase assessed as inhibition of [14C]-deoxycorticosterone hydroxylation at 2 uM
|
Bos taurus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.
Year : 1977
Volume : 20
Issue : 6
First Page : 762
Last Page : 766
Authors : Napoli JL, Counsell RE.
Abstract : A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.
Inhibition of bovine adrenal gland 11beta-hydroxylase assessed as inhibition of [14C]-deoxycorticosterone hydroxylation
|
Bos taurus
|
580.0
nM
|
|
Journal : J. Med. Chem.
Title : New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.
Year : 1977
Volume : 20
Issue : 6
First Page : 762
Last Page : 766
Authors : Napoli JL, Counsell RE.
Abstract : A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.
Inhibition of bovine adrenal gland 11beta-hydroxylase assessed as amount of corticosterone production using 22 nmol [14C]-deoxycorticosterone measured per 5 mins at 2 nmol
|
Bos taurus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.
Year : 1977
Volume : 20
Issue : 6
First Page : 762
Last Page : 766
Authors : Napoli JL, Counsell RE.
Abstract : A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.
Inhibition of bovine adrenal gland 11beta-hydroxylase assessed as amount of corticosterone production using 11 nmol [14C]-deoxycorticosterone measured per 5 mins at 2 nmol
|
Bos taurus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.
Year : 1977
Volume : 20
Issue : 6
First Page : 762
Last Page : 766
Authors : Napoli JL, Counsell RE.
Abstract : A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.
Inhibition of human CYP11B1 expressed in hamster V79MZh cells using [1,2-3H]-11-deoxycorticosterone as substrate
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent 11β-hydroxylase inhibitors with inverse metabolic stability in human plasma and hepatic S9 fractions to promote wound healing.
Year : 2014
Volume : 57
Issue : 18
First Page : 7811
Last Page : 7817
Authors : Zhu W, Hu Q, Hanke N, van Koppen CJ, Hartmann RW.
Abstract : Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50 = 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2 ≫ 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).
Inhibition of human CYP17 expressed in Escherichia coli using progesterone as substrate at 2 uM
|
Homo sapiens
|
3.0
%
|
|
Journal : J. Med. Chem.
Title : Potent 11β-hydroxylase inhibitors with inverse metabolic stability in human plasma and hepatic S9 fractions to promote wound healing.
Year : 2014
Volume : 57
Issue : 18
First Page : 7811
Last Page : 7817
Authors : Zhu W, Hu Q, Hanke N, van Koppen CJ, Hartmann RW.
Abstract : Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50 = 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2 ≫ 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).
Inhibition of human placental CYP19 using [1beta-3H]androstenedione as substrate at 2 uM by 3H2O-method
|
Homo sapiens
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Potent 11β-hydroxylase inhibitors with inverse metabolic stability in human plasma and hepatic S9 fractions to promote wound healing.
Year : 2014
Volume : 57
Issue : 18
First Page : 7811
Last Page : 7817
Authors : Zhu W, Hu Q, Hanke N, van Koppen CJ, Hartmann RW.
Abstract : Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50 = 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2 ≫ 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).
Inhibition of human CYP11B2 expressed in hamster V79MZh cells using [1,2-3H]-11-deoxycorticosterone as substrate
|
Homo sapiens
|
72.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent 11β-hydroxylase inhibitors with inverse metabolic stability in human plasma and hepatic S9 fractions to promote wound healing.
Year : 2014
Volume : 57
Issue : 18
First Page : 7811
Last Page : 7817
Authors : Zhu W, Hu Q, Hanke N, van Koppen CJ, Hartmann RW.
Abstract : Topical application of CYP11B1 inhibitors to reduce cutaneous cortisol is a novel strategy to promote healing of chronic wounds. Pyridyl substituted arylsulfonyltetrahydroquinolines were designed and synthesized resulting in a strong inhibitor 34 (IC50 = 5 nM). It showed no inhibition of CYP17 and CYP19 and no mutagenic effects. It exhibited inverse metabolic stability in plasma (t1/2 ≫ 150 min), which is similar to wound fluid in composition, and in liver S9 fractions (t1/2 = 16 min).
Inhibition of human placental microsomal CYP19 using [1beta-3H]androstenedione substrate pre-incubated for 5 mins by scintillation counting method
|
Homo sapiens
|
0.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Year : 2015
Volume : 89
First Page : 106
Last Page : 114
Authors : Stefanachi A, Hanke N, Pisani L, Leonetti F, Nicolotti O, Catto M, Cellamare S, Hartmann RW, Carotti A.
Abstract : Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
Inhibition of human CYP17 expressed in Escherichia coli using [3H]-progesterone substrate pre-incubated for 5 mins at 2.5 uM in presence of rat P450 reductase by HPLC method
|
Homo sapiens
|
3.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Year : 2015
Volume : 89
First Page : 106
Last Page : 114
Authors : Stefanachi A, Hanke N, Pisani L, Leonetti F, Nicolotti O, Catto M, Cellamare S, Hartmann RW, Carotti A.
Abstract : Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
Inhibition of human CYP11B1 expressed in hamster V79MZh11B1 cells using [1,2-3H]-11-deoxycorticosterone substrate incubated for 25 mins by HPLC method
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Year : 2015
Volume : 89
First Page : 106
Last Page : 114
Authors : Stefanachi A, Hanke N, Pisani L, Leonetti F, Nicolotti O, Catto M, Cellamare S, Hartmann RW, Carotti A.
Abstract : Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
Inhibition of human CYP11B2 expressed in hamster V79MZh11B2 cells using [1,2-3H]-11-deoxycorticosterone substrate incubated for 25 mins by HPLC method
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Year : 2015
Volume : 89
First Page : 106
Last Page : 114
Authors : Stefanachi A, Hanke N, Pisani L, Leonetti F, Nicolotti O, Catto M, Cellamare S, Hartmann RW, Carotti A.
Abstract : Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
Inhibition of human aldosterone synthase expressed in V79 MZ cells pretreated with compound for 1 hr followed by addition of 500 nM 11-deoxycorticosterone for 1hr by HPLC analysis
|
Homo sapiens
|
208.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldosterone synthase inhibitors as promising treatments for mineralocorticoid dependent cardiovascular and renal diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5011
Last Page : 5022
Authors : Hu Q, Yin L, Hartmann RW.
Abstract : Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and volume, recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathological circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clinical trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.
Inhibition of human CYP11B1 expressed in V79 MZ cells pretreated with compound for 1 hr followed by addition of 500 nM 11-deoxycorticosterone for 3 hrs by HPLC analysis
|
Homo sapiens
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Aldosterone synthase inhibitors as promising treatments for mineralocorticoid dependent cardiovascular and renal diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5011
Last Page : 5022
Authors : Hu Q, Yin L, Hartmann RW.
Abstract : Besides the well-known roles of aldosterone as a mineralocorticoid in regulating homeostasis of electrolytes and volume, recent studies revealed that it is also a potent proinflammation factor inducing reactive oxygen species and up-regulating a panel of fibrosis related genes. Under pathological circumstances, excessive aldosterone is involved in a lot of chronic diseases, including hypertension, cardiac fibrosis, congestive heart failure, ventricular remodeling, and diabetic nephropathy. Therefore, the inhibition of aldosterone synthase (CYP11B2), which is the pivotal enzyme in aldosterone biosynthesis, was proposed as a superior approach. Expected pharmacodynamic effects have been demonstrated in both animal models and clinical trials after the application of CYP11B2 inhibitors. The importance of selectivity over other steroidogenic CYP enzymes, in particular 11β-hydroxylase (CYP11B1), was also revealed. Recently, much more selective CYP11B2 inhibitors have been reported, which could be promising drug candidates for the treatment of aldosterone related diseases.
Inhibition of human CYP11B1 expressed in hamster fibroblast using 100 nM [3H]-11-deoxycorticosterone as substrate after 25 mins by HPLC analysis
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.
Year : 2015
Volume : 96
First Page : 139
Last Page : 150
Authors : Hu Q, Kunde J, Hanke N, Hartmann RW.
Abstract : The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.
Inhibition of human CYP11B2 expressed in hamster fibroblast using 100 nM [3H]-11-deoxycorticosterone as substrate after 45 mins by HPLC analysis
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.
Year : 2015
Volume : 96
First Page : 139
Last Page : 150
Authors : Hu Q, Kunde J, Hanke N, Hartmann RW.
Abstract : The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.
Cellular Inhibition Assay: V79MZ cells expressing human CYP11B1 and human CYP11B2 genes, respectively, were grown on 24-well cell culture plates (8×10^5 cells per well) with 1.9 cm^2 culture area per well in 1 ml DMEM culture medium until confluence. Before testing, the DMEM culture medium was removed and 450 μl of fresh DMEM, containing the inhibitor in at least three different concentrations for determining the IC50 value, was added to each well. Every value was determined at least three times. After a pre-incubation step of 60 min at 37° C., the reaction was started by the addition of 50 μl of DMEM containing the substrate 11-deoxycorticosterone (containing 0.15 μCi of [1,2-3H] 11-deoxycorticosterone, dissolved in ethanol, final concentration 100 nM). The V79MZh11B1 cells were incubated for 25 min, the V79MZh11B2 cells were incubated for 50 min. Controls were treated in the same way without inhibitors. The maximum DMSO concentration in each well was 1%. Enzyme reactions were stopped by extracting the supernatant with 500 μl ethyl acetate. Samples were centrifuged (10000×g, 2 min), and the solvent was pipetted into fresh cups. The solvent was evaporated and the steroids were redissolved in 40 μl of methanol and analyzed by HPLC using radioflow detection (Ehmer et al. J. Steroid Biochem. Mol. Biol. 2002, 81, 173-179 and Denner et al. Endocr. Res. 1995, 21, 443-448).
|
Homo sapiens
|
15.0
nM
|
|
Title : Selective CYP11B1 inhibitors for the treatment of cortisol dependent diseases
Year : 2016
Cellular Inhibition Assay: V79MZ cells expressing human CYP11B1 and human CYP11B2 genes, respectively, were grown on 24-well cell culture plates (8×10^5 cells per well) with 1.9 cm^2 culture area per well in 1 ml DMEM culture medium until confluence. Before testing, the DMEM culture medium was removed and 450 μl of fresh DMEM, containing the inhibitor in at least three different concentrations for determining the IC50 value, was added to each well. Every value was determined at least three times. After a pre-incubation step of 60 min at 37° C., the reaction was started by the addition of 50 μl of DMEM containing the substrate 11-deoxycorticosterone (containing 0.15 μCi of [1,2-3H] 11-deoxycorticosterone, dissolved in ethanol, final concentration 100 nM). The V79MZh11B1 cells were incubated for 25 min, the V79MZh11B2 cells were incubated for 50 min. Controls were treated in the same way without inhibitors. The maximum DMSO concentration in each well was 1%. Enzyme reactions were stopped by extracting the supernatant with 500 μl ethyl acetate. Samples were centrifuged (10000×g, 2 min), and the solvent was pipetted into fresh cups. The solvent was evaporated and the steroids were redissolved in 40 μl of methanol and analyzed by HPLC using radioflow detection (Ehmer et al. J. Steroid Biochem. Mol. Biol. 2002, 81, 173-179 and Denner et al. Endocr. Res. 1995, 21, 443-448).
|
Homo sapiens
|
72.0
nM
|
|
Title : Selective CYP11B1 inhibitors for the treatment of cortisol dependent diseases
Year : 2016
Inhibition of human CYP11B1 expressed in hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate after 6 hrs by HPLC analysis
|
Homo sapiens
|
15.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease.
Year : 2017
Volume : 60
Issue : 12
First Page : 5086
Last Page : 5098
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Hu Q, Siebenbürger L, Boerger C, Scheuer C, Laschke MW, Menger MD, Hartmann RW.
Abstract : Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3-phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 μM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study.
Inhibition of human CYP11B2 expressed in hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate after 6 hrs by HPLC analysis
|
Homo sapiens
|
72.0
nM
|
|
Journal : J Med Chem
Title : Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease.
Year : 2017
Volume : 60
Issue : 12
First Page : 5086
Last Page : 5098
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Hu Q, Siebenbürger L, Boerger C, Scheuer C, Laschke MW, Menger MD, Hartmann RW.
Abstract : Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3-phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 μM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study.
Inhibition of human CYP11B1 expressed in hamster V79MZ cells using [1,2-3H]-11-deoxycorticosterone as substrate after 6 hrs by HPTLC analysis
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
Year : 2018
Volume : 143
First Page : 591
Last Page : 597
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Engeli RT, Hu Q, Odermatt A, Hartmann RW.
Abstract : Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
Inhibition of human placental microsomal CYP19A1 at 2 uM using [1beta-3H]androstenedione after 21 mins by liquid scintillation spectrometry
|
Homo sapiens
|
0.0
%
|
|
Journal : Eur J Med Chem
Title : Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
Year : 2018
Volume : 143
First Page : 591
Last Page : 597
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Engeli RT, Hu Q, Odermatt A, Hartmann RW.
Abstract : Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
Inhibition of human CYP17A1 expressed in Escherichia coli XL1 at 2 uM using [3H]-progesterone as substrate preincubated with substrate for 5 mins measured after 45 mins by HPLC analysis
|
Homo sapiens
|
3.0
%
|
|
Journal : Eur J Med Chem
Title : Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
Year : 2018
Volume : 143
First Page : 591
Last Page : 597
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Engeli RT, Hu Q, Odermatt A, Hartmann RW.
Abstract : Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
Inhibition of human 11beta-HSD1 expressed in HEK293 cell lysates at 200 uM using [1,2-3H]-cortisone as substrate preincubated for 10 mins followed by substrate addition in presence of NADPH by scintillation counting relative to control
|
Homo sapiens
|
70.0
%
|
|
Journal : Eur J Med Chem
Title : Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
Year : 2018
Volume : 143
First Page : 591
Last Page : 597
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Engeli RT, Hu Q, Odermatt A, Hartmann RW.
Abstract : Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
Inhibition of human 11beta-HSD1 expressed in HEK293 cell lysates at 50 uM using [1,2-3H]-cortisone as substrate preincubated for 10 mins followed by substrate addition in presence of NADPH by scintillation counting relative to control
|
Homo sapiens
|
54.0
%
|
|
Journal : Eur J Med Chem
Title : Accelerated skin wound healing by selective 11β-Hydroxylase (CYP11B1) inhibitors.
Year : 2018
Volume : 143
First Page : 591
Last Page : 597
Authors : Emmerich J, van Koppen CJ, Burkhart JL, Engeli RT, Hu Q, Odermatt A, Hartmann RW.
Abstract : Previous studies have shown that inhibition of cortisol biosynthesis in skin leads to accelerated wound healing. Here, pyridylmethyl pyridine type 11β-hydroxylase (CYP11B1) inhibitors were optimized for topical application to avoid systemic side effects. The resulting very potent, non-toxic CYP11B1 inhibitor 14 (IC50 = 0.8 nM) exhibited good selectivity over 11β-HSD1, CYP17A1 and CYP19A1. The compound showed high stability toward human plasma (t1/2= > 150 min, as a substitute for wound fluid) and low stability toward HLS9 (t1/2 = 19 min) for rapid metabolic clearance after absorption. Compound 14 was able to accelerate wound healing in human skin.
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
4.18
%
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
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Escherichia coli
|
6.34
%
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
19.17
%
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
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Pseudomonas aeruginosa
|
18.6
%
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
20.43
%
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
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Candida albicans
|
2.49
%
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-9.27
%
|
|
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
|
-2.14
%
|
|
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.
Inhibition of cytochrome P450 in Sprague-Dawley rat liver microsomes assessed as inhibition of NADPH-dependent retinoic acid oxidation at 100 uM incubated for 5 mins followed by retinoic acid addition and further incubated for 60 mins by HPLC analysis relative to control
|
Rattus norvegicus
|
47.0
%
|
|
Title : Method for treating skin with retinoids and retinoid boosters
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.25
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.65
%
|
|
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
|
0.19
%
|
|
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
|
0.03
%
|
|
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
|
0.19
%
|
|
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
|
0.03
%
|
|
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.