In vitro antagonist activity against rat prostatic androgen receptor (AR)
|
None
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.
Year : 1986
Volume : 29
Issue : 11
First Page : 2298
Last Page : 2315
Authors : Rasmusson GH, Reynolds GF, Steinberg NG, Walton E, Patel GF, Liang T, Cascieri MA, Cheung AH, Brooks JR, Berman C.
Abstract : A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.
Binding affinity against rat prostate cytosolic Androgen receptor using [3H]mibolerone as radioligand
|
None
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity studies of side-chain derivatized arylhydantoins for investigation as androgen receptor radioligands.
Year : 2001
Volume : 11
Issue : 8
First Page : 1045
Last Page : 1047
Authors : Van Dort ME, Jung YW.
Abstract : A series of arylhydantoin derivatives modeled after the antiandrogen RU 58841 was generated to identify potential candidates for development as androgen receptor (AR) radioligands. Side-chain modified derivatives of RU 58841, suitable for labeling with either carbon-11 or radiohalogens (fluorine-18, iodine-123), were synthesized and tested for their AR binding affinities. The N-(iodopropenyl) derivative 13 (Ki = 13 nM) is a potential candidate for development as a radioiodinated AR ligand.
Inhibitory constant against rat prostate cytosol androgen receptor using [3H]mibolerone
|
Rattus norvegicus
|
1.4
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and pharmacological characterization of 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a high-affinity nonsteroidal androgen receptor ligand.
Year : 2000
Volume : 43
Issue : 17
First Page : 3344
Last Page : 3347
Authors : Van Dort ME, Robins DM, Wayburn B.
Abstract : 4-[4, 4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-+ ++trif luoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-i odo benzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K(i) = 0.71 +/- 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5alpha-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.
Binding affinity to human CBG receptor (corticosteroid-binding globulins)
|
None
|
190.55
nM
|
|
Journal : J. Med. Chem.
Title : Comparative molecular active site analysis (CoMASA). 1. An approach to rapid evaluation of 3D QSAR.
Year : 2004
Volume : 47
Issue : 11
First Page : 2732
Last Page : 2742
Authors : Kotani T, Higashiura K.
Abstract : We have developed a rapid evaluation method, comparative molecular active site analysis (CoMASA), for obtaining 3D QSAR. CoMASA has three major advantages: (1) the CoMASA results would easily transform to pharmacophore and/or queries required for 3D database searches, (2) the CoMASA method is not required to consider orientation and translation of molecules against a lattice, and (3) standard PCs can be used to perform the analysis. The potential of these improvements and possible further enhancements are discussed.
Inhibition of human placental aromatase Cytochrome P450 19A1
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Analogues of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage.
Year : 1983
Volume : 26
Issue : 1
First Page : 50
Last Page : 54
Authors : Foster AB, Jarman M, Leung CS, Rowlands MG, Taylor GN.
Abstract : In our probing of the structural features responsible for the inhibitory activity of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] toward the cholesterol side-chain cleavage enzyme system desmolase and the estrogen-forming system aromatase, targets in the action of 1 against hormone-dependent mammary tumors, analogues in several categories have been synthesized and evaluated. Of the known monoamino derivatives, the meta derivative [2, 3-(3-aminophenyl)-3-ethylpiperidine-2,6-dione] was as inhibitory toward desmolase as 1, and the N-amino analogue [4, 1-amino-3-ethyl-3-phenylpiperidine-2,6-dione] was three times as inhibitory (respective Ki values of 1, 2, and 4 are 14, 13, and 4.6 microM), but 2 was a weak inhibitor and 4 was a noninhibitor of aromatase. Another amino analogue [5, 5-amino-3-ethyl-3-phenylpiperidine-2,6-dione] inhibited neither enzyme system. Reaction of glutethimide (11) with hydrazine and thermal cyclization of the resulting amide hydrazide (15) afforded an improved synthesis of 4. Analogues having a second amino substituent, either at C-5 (10) or at N-1 (14) of the piperidine-2,6-dione residue, were less inhibitory than was 1 toward desmolase and aromatase. Among analogues having little or no inhibitory activity were hydroxy derivatives of 1 and 2, namely, 3-(4-amino-3-hydroxyphenyl)-3-ethylpiperidine-2,6-dione (20) and the 3-amino-4-hydroxy analogue (21).
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
21.7
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
Inhibition of rat prostate cytosolic androgen receptor
|
Rattus norvegicus
|
4.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity investigation of iodinated arylhydantoins and arylthiohydantoins for development as androgen receptor radioligands.
Year : 2004
Volume : 14
Issue : 21
First Page : 5285
Last Page : 5288
Authors : Van Dort ME, Jung YW.
Abstract : A series of side-chain derivatives of the arylhydantoin RU 58841 and the arylthiohydantoin RU 59063, wherein the aromatic trifluoromethyl group was replaced with iodine, was synthesized for possible development as radioiodinated androgen receptor (AR) ligands. Derivatives containing the cyanomethyl, methoxyethyl and propenyl side-chains displayed moderately high affinity (K(i)=20-59nM) towards the rat AR. Side-chains containing bulky lipophilic groups such as, benzyl and phenylpropyl, were poorly tolerated (K(i)>219nM). Superior AR binding affinities (0.71nM<K(i)<11nM) were displayed by arylhydantoins and arylthiohydantoin derivatives containing hydroxybutyl or methyl side-chains. The latter compounds are potential candidates for development as radioiodinated AR ligands.
Inhibition of [3H]mibolerone binding to cytosolic androgen receptor of rat ventral prostate
|
Rattus norvegicus
|
1.413
nM
|
|
Journal : J. Med. Chem.
Title : Three-dimensional structure-activity relationships of nonsteroidal ligands in complex with androgen receptor ligand-binding domain.
Year : 2005
Volume : 48
Issue : 4
First Page : 917
Last Page : 925
Authors : Söderholm AA, Lehtovuori PT, Nyrönen TH.
Abstract : We studied the three-dimensional quantitative structure-activity relationships (3D QSAR) of 70 structurally and functionally diverse androgen receptor (AR) binding compounds using the comparative molecular similarity indices analysis (CoMSIA) method. The compound set contained 67 nonsteroidal analogues of flutamide, nilutamide, and bicalutamide whose binding mode to AR was unknown. Docking was used to identify the preferred binding modes for the nonsteroidal compounds within the AR ligand-binding pocket (LBP) and to generate the ligand alignment for the 3D QSAR analysis. The alignment produced a statistically significant and predictive model, validated by random group cross-validation and external test sets (q(2)(LOO) = 0.656, SDEP = 0.576, r(2) = 0.911, SEE = 0.293; q(2)(10) = 0.612, q(2)(5) = 0.571; pred-r(2) = 0.800). Additional model validation comes from the CoMSIA maps that were interpreted with respect to the LBP structure. The model takes into account and links the AR LBP structure, docked ligand structures, and the experimental binding activities. The results provide valuable information on intermolecular interactions between nonsteroidal ligands and the AR LBP.
Inhibition of human androgen receptor expressed in Escherichia coli
|
Homo sapiens
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : 11beta-alkyl-Delta9-19-nortestosterone derivatives: high-affinity ligands and potent partial agonists of the androgen receptor.
Year : 2004
Volume : 47
Issue : 21
First Page : 4985
Last Page : 4988
Authors : Muddana SS, Price AM, MacBride MM, Peterson BR.
Abstract : We report the synthesis of novel steroidal androgen receptor ligands comprising 11beta-alkyl-Delta(9)-derivatives of 19-nortestosterone. These compounds are structurally related to the antiprogestin, antiglucocorticoid, and antiandrogen drug mifepristone (RU486). Nortestosterone analogues bearing 11beta-octyl and 11beta-decyl side-chains bind tightly to recombinant AR protein (IC(50) = 6.6 nM and IC(50) = 0.8 nM), block AR dimerization, exhibit activity against LNCaP prostate cancer cells, and comprise partial AR agonists with low antiglucocorticoid activity.
Inhibitory activity against AR
|
Homo sapiens
|
2.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Androstenediol analogs as ER-beta-selective SERMs.
Year : 2006
Volume : 16
Issue : 4
First Page : 834
Last Page : 838
Authors : Blizzard TA, Gude C, Morgan JD, Chan W, Birzin ET, Mojena M, Tudela C, Chen F, Knecht K, Su Q, Kraker B, Mosley RT, Holmes MA, Sharma N, Fitzgerald PM, Rohrer SP, Hammond ML.
Abstract : A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Displacement of [3H]DHT from human SHBG
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Progressive docking: a hybrid QSAR/docking approach for accelerating in silico high throughput screening.
Year : 2006
Volume : 49
Issue : 25
First Page : 7466
Last Page : 7478
Authors : Cherkasov A, Ban F, Li Y, Fallahi M, Hammond GL.
Abstract : A combination of protein-ligand docking and ligand-based QSAR approaches has been elaborated, aiming to speed-up the process of virtual screening. In particular, this approach utilizes docking scores generated for already processed compounds to build predictive QSAR models that, in turn, assess hypothetical target binding affinities for yet undocked entries. The "progressive docking" has been tested on drug-like substances from the NCI database that have been docked into several unrelated targets, including human sex hormone binding globulin (SHBG), carbonic anhydrase, corticosteroid-binding globulin, SARS 3C-like protease, and HIV1 reverse transcriptase. We demonstrate that progressive docking can reduce the amount of computations 1.2- to 2.6-fold (when compared to traditional docking), while maintaining 80-99% hit recovery rates. This progressive-docking procedure, therefore, substantially accelerates high throughput screening, especially when using high accuracy (slower) docking approaches and large-sized datasets, and has allowed us to identify several novel potent nonsteroidal SHBG ligands.
Binding affinity to androgen receptor
|
None
|
2.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bridged androstenediol analogs as ER-beta selective SERMs.
Year : 2007
Volume : 17
Issue : 10
First Page : 2944
Last Page : 2948
Authors : Blizzard TA, Gude C, Chan W, Birzin ET, Mojena M, Tudela C, Chen F, Knecht K, Su Q, Kraker B, Holmes MA, Rohrer SP, Hammond ML.
Abstract : A series of bridged androstenediol derivatives was prepared. The bridged compounds exhibited reduced ER-beta selectivity relative to uncyclized analogs.
Binding affinity at AR
|
None
|
2.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Androstene-3,5-dienes as ER-beta selective SERMs.
Year : 2007
Volume : 17
Issue : 22
First Page : 6295
Last Page : 6298
Authors : Blizzard TA, Gude C, Morgan JD, Chan W, Birzin ET, Mojena M, Tudela C, Chen F, Knecht K, Su Q, Kraker B, Mosley RT, Holmes MA, Rohrer SP, Hammond ML.
Abstract : A series of androstene-3,5-diene derivatives were prepared. Despite lacking the C-3 hydroxyl previously believed necessary for ER activity, some of the analogs retained surprising affinity for ER-beta. For example, diene 4 retained excellent selectivity and potency as an ER-beta agonist and was more selective for ER-beta over the androgen receptor (AR).
Displacement of [3H]5alpha dihydrotestosterone from human sex hormone binding globulin
|
Homo sapiens
|
0.631
nM
|
|
Journal : J. Med. Chem.
Title : An updated steroid benchmark set and its application in the discovery of novel nanomolar ligands of sex hormone-binding globulin.
Year : 2008
Volume : 51
Issue : 7
First Page : 2047
Last Page : 2056
Authors : Cherkasov A, Ban F, Santos-Filho O, Thorsteinson N, Fallahi M, Hammond GL.
Abstract : A benchmark data set of steroids with known affinity for sex hormone-binding globulin (SHBG) has been widely used to validate popular molecular field-based QSAR techniques. We have expanded the data set by adding a number of nonsteroidal SHBG ligands identified both from the literature and in our previous experimental studies. This updated molecular set has been used herein to develop 4D QSAR models based on "inductive" descriptors and to gain insight into the molecular basis of protein-ligand interactions. Molecular alignment was generated by means of docking active compounds into the active site of the SHBG. Surprisingly, the alignment of the benchmark steroids contradicted the classical ligand-based alignment utilized in previous CoMFA and CoMSIA models yet afforded models with higher statistical significance and predictive power. The resulting QSAR models combined with CoMFA and CoMSiA models as well as structure-based virtual screening allowed discovering several low-micromolar to nanomolar nonsteroidal inhibitors for human SHBG.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM Miconazole
|
Homo sapiens
|
41.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM Miconazole
|
Homo sapiens
|
10.5
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM Miconazole
|
Homo sapiens
|
4.38
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM deoxypodophyllotoxin
|
Homo sapiens
|
61.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM deoxypodophyllotoxin
|
Homo sapiens
|
10.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM deoxypodophyllotoxin
|
Homo sapiens
|
4.85
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM epipodophyllotoxin
|
Homo sapiens
|
69.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM epipodophyllotoxin
|
Homo sapiens
|
7.96
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM epipodophyllotoxin
|
Homo sapiens
|
11.46
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM podophyllotoxin
|
Homo sapiens
|
44.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM podophyllotoxin
|
Homo sapiens
|
7.82
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM podophyllotoxin
|
Homo sapiens
|
7.04
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM demethylene-deoxy-podophyllotoxin
|
Homo sapiens
|
103.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM demethylene-deoxy-podophyllotoxin
|
Homo sapiens
|
69.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM demethylene-deoxy-podophyllotoxin
|
Homo sapiens
|
69.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 1 uM demethylenepodophyllotoxin
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 10 uM demethylenepodophyllotoxin
|
Homo sapiens
|
98.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Activity of human recombinant CYP3A4 assessed as conversion of testosterone to 6-beta-hydroxytestesterone at 25 uM after 60 mins in presence of 25 uM demethylenepodophyllotoxin
|
Homo sapiens
|
97.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation.
Year : 2008
Volume : 43
Issue : 6
First Page : 1171
Last Page : 1179
Authors : Julsing MK, Vasilev NP, Schneidman-Duhovny D, Muntendam R, Woerdenbag HJ, Quax WJ, Wolfson HJ, Ionkova I, Kayser O.
Abstract : Deoxypodophyllotoxin is stereoselectively converted into epipodophyllotoxin by recombinant human cytochrome P450 3A4 (CYP3A4). Further kinetic analysis revealed that the Michaelis-Menten K(m) and V(max) for hydroxylation of deoxypodophyllotoxin by CYP3A4 at C7 position were 1.93 microM and 1.48 nmol/min/nmol, respectively. Deoxypodophyllotoxin was subjected to automated docking analysis in order to get better knowledge of the interaction between the CYP3A4 enzyme and the substrate, using the PatchDock algorithm with distance constraints. Automated docking showed that the beta-hydrogen atom at C7 position is in the most appropriate binding orientation at the site of oxidation. The docking results are consistent with the experimental data for the bioconversion of deoxypodophyllotoxin into epipodophyllotoxin by CYP3A4. In addition, the effects of five lignans, deoxypodophyllotoxin, epipodophyllotoxin, podophyllotoxin, demethylenedeoxypodophyllotoxin, and demethylenepodophyllotoxin, on CYP3A4 were compared in order to investigate the influence of the methylenedioxy group on the biotransformation process, to give insight into the mode of metabolization and to explain inhibitory activity of lignans.
Agonist activity at androgen receptor in mouse NIH3T3 cells transiently transfected with beta-galactosidase reporter gene assessed as cellular transformation by R-SAT assay
|
Mus musculus
|
1.995
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.
Year : 2009
Volume : 52
Issue : 22
First Page : 7186
Last Page : 7191
Authors : Schlienger N, Lund BW, Pawlas J, Badalassi F, Bertozzi F, Lewinsky R, Fejzic A, Thygesen MB, Tabatabaei A, Bradley SR, Gardell LR, Piu F, Olsson R.
Abstract : Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.
Agonist activity at androgen receptor in human MDA-KB2 cells transfected with MMTV linked luciferase assessed as transcriptional activation by luciferase reporter gene assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators.
Year : 2009
Volume : 52
Issue : 22
First Page : 7186
Last Page : 7191
Authors : Schlienger N, Lund BW, Pawlas J, Badalassi F, Bertozzi F, Lewinsky R, Fejzic A, Thygesen MB, Tabatabaei A, Bradley SR, Gardell LR, Piu F, Olsson R.
Abstract : Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.
Inhibition of human 17beta-HSD7 expressed in HEK293 cells assessed as inhibition of reduction of [14C]estrone into [14C]estradiol at 3 uM after 7 hrs
|
Homo sapiens
|
7.5
%
|
|
Journal : J. Med. Chem.
Title : Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.
Year : 2009
Volume : 52
Issue : 23
First Page : 7488
Last Page : 7502
Authors : Bellavance E, Luu-The V, Poirier D.
Abstract : 17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM). Inhibition assays with 17beta-HSD1, 17beta-HSD5, 5alpha-reductase (5alpha-R) 1 and 5alpha-R2 revealed that 17beta-HSD7 inhibitors with a 4-methyl-4-aza nucleus were also able to inhibit 5alpha-Rs but not the other enzymes tested. Two 4-aza-5alpha-androstane inhibitors were, however, selective and still showed good inhibition of 17beta-HSD7. First selective and efficient inhibitors of 17beta-HSD7 are now available for additional mechanistic and therapeutic studies.
Binding affinity to androgen receptor by fluorescence binding assay
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of potent, substituted carbazoles as selective androgen receptor modulators (SARMs).
Year : 2010
Volume : 20
Issue : 24
First Page : 7516
Last Page : 7520
Authors : Miller CP, Bhaket P, Muthukaman N, Lyttle CR, Shomali M, Gallacher K, Slocum C, Hattersley G.
Abstract : The synthesis and in vitro binding affinity for a novel series of potent androgen receptor modulators is described. One of the more potent compounds (17, RAD35010) was further characterized in vivo where it restored levator ani weight in castrated male rats to near sham level while having no significant effect on prostate weight.
Displacement of fluorescent-tagged R1881 from androgen receptor after 4 hrs by fluorometric assay
|
None
|
29.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis, and Preclinical Characterization of the Selective Androgen Receptor Modulator (SARM) RAD140.
Year : 2011
Volume : 2
Issue : 2
First Page : 124
Last Page : 129
Authors : Miller CP, Shomali M, Lyttle CR, O'Dea LS, Herendeen H, Gallacher K, Paquin D, Compton DR, Sahoo B, Kerrigan SA, Burge MS, Nickels M, Green JL, Katzenellenbogen JA, Tchesnokov A, Hattersley G.
Abstract : This report describes the discovery of RAD140, a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM). The characterization of RAD140 in several preclinical models of anabolic androgen action is also described.
DRUGMATRIX: Progesterone radioligand binding (ligand: [3H] R-5020)
|
Bos taurus
|
252.0
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
DRUGMATRIX: Androgen (Testosterone) AR radioligand binding (ligand: [3H] Mibolerone)
|
Escherichia coli
|
6.169
nM
|
|
DRUGMATRIX: Androgen (Testosterone) AR radioligand binding (ligand: [3H] Mibolerone)
|
Escherichia coli
|
4.112
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
Displacement of [3H]R1881 from wild type human androgen receptor expressed in COS-1 cells co-transfected with pSG5 after 15 mins by scintillation assay relative to untreated control
|
Homo sapiens
|
0.1
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.
Year : 2012
Volume : 55
Issue : 14
First Page : 6316
Last Page : 6327
Authors : Poutiainen PK, Oravilahti T, Peräkylä M, Palvimo JJ, Ihalainen JA, Laatikainen R, Pulkkinen JT.
Abstract : We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.
Displacement of [3H]R1881 from wild type human androgen receptor expressed in COS-1 cells co-transfected with pSG5 after 15 mins by scintillation assay
|
Homo sapiens
|
4.571
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.
Year : 2012
Volume : 55
Issue : 14
First Page : 6316
Last Page : 6327
Authors : Poutiainen PK, Oravilahti T, Peräkylä M, Palvimo JJ, Ihalainen JA, Laatikainen R, Pulkkinen JT.
Abstract : We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
33.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
37.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-175.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
Displacement of [3H]Mibolerone from rat recombinant androgen receptor expressed in Escherichia coli after 4 hrs
|
Rattus norvegicus
|
4.3
nM
|
|
Displacement of [3H]Mibolerone from rat recombinant androgen receptor expressed in Escherichia coli after 4 hrs
|
Rattus norvegicus
|
6.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
Displacement of [3H]Mibolerone from rat recombinant androgen receptor expressed in Escherichia coli at 10 uM after 4 hrs relative to control
|
Rattus norvegicus
|
2.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
79.99
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
92.19
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
Antagonist activity against pSG5-tagged human androgen receptor expressed in COS1 cells assessed as reduction in receptor-mediated transcriptional activity by AR-regulated rat probasin promoter fragment driven firefly luciferase reporter assay
|
Homo sapiens
|
4.17
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
Displacement of [3H]R1881 from pSG5-tagged human androgen receptor expressed in COS1 cells assessed as relative binding inhibition
|
Homo sapiens
|
4.27
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
Antagonist activity against pSG5-tagged human androgen receptor expressed in COS1 cells assessed as receptor-mediated testosterone-induced transcriptional activity at 10 uM by AR-regulated rat probasin promoter fragment driven firefly luciferase reporter assay (Rvb = 100 +/- 5.7%)
|
Homo sapiens
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of second-generation tropanol-based androgen receptor modulators.
Year : 2015
Volume : 58
Issue : 3
First Page : 1569
Last Page : 1574
Authors : Sundén H, Holland MC, Poutiainen PK, Jääskeläinen T, Pulkkinen JT, Palvimo JJ, Olsson R.
Abstract : To circumvent antiandrogen resistance in prostate cancer, antiandrogens effective for both the androgen receptor (AR) and AR mutants are required. The AR antagonists in this study originate from previous findings, which showed that subtle differences in substitution pattern lead to a conformational change that alters the ligand activity, rendering an agonist to an antagonist. We have identified small yet potent tropanol-based ligands possessing significant antiandrogenic activity with both wild-type AR and the two most common AR ligand binding domain (LBD) mutants.
Inhibition of L-type calcium channel measured using 2-electrode voltage-clamp in human embryonic kidney cells heterologically expressing alpha-1C subunit
|
Homo sapiens
|
34.0
nM
|
|
Journal : Journal of Applied Toxicology
Title : Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment.
Year : 2012
Volume : 32
First Page : 858
Last Page : 866
Authors : Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S.
Abstract : Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-à-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug-multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC₅₀ values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable.
Inhibition of L-type calcium channel measured using 2-electrode voltage-clamp in human embryonic kidney cells heterologically expressing alpha-1C subunit
|
Homo sapiens
|
38.4
nM
|
|
Journal : Journal of Applied Toxicology
Title : Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment.
Year : 2012
Volume : 32
First Page : 858
Last Page : 866
Authors : Wiśniowska B, Mendyk A, Fijorek K, Glinka A, Polak S.
Abstract : Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-à-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug-multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC₅₀ values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable.
Androgenic activity at human androgen receptor expressed in African green monkey CV-1 cells assessed as increase in interaction between VP16-fused AR-NTD and GAL4-fused AR-LBD after 17 hrs by luciferase reporter gene assay
|
Homo sapiens
|
1.1
nM
|
|
Journal : J Med Chem
Title : Structure-Based Approach To Identify 5-[4-Hydroxyphenyl]pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators.
Year : 2017
Volume : 60
Issue : 14
First Page : 6451
Last Page : 6457
Authors : Unwalla R, Mousseau JJ, Fadeyi OO, Choi C, Parris K, Hu B, Kenney T, Chippari S, McNally C, Vishwanathan K, Kilbourne E, Thompson C, Nagpal S, Wrobel J, Yudt M, Morris CA, Powell D, Gilbert AM, Chekler ELP.
Abstract : In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
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
|
-3.69
%
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-8.96
%
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.5
%
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
-7.2
%
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
8.83
%
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.12
%
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
1.59
%
|
|