|
Inhibition of MAMC O-dealkylation mediated by human Cytochrome P450 2D6 expressed in human lymphoblastoid cell line
|
Homo sapiens
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities.
Year : 2003
Volume : 46
Issue : 1
First Page : 74
Last Page : 86
Authors : Venhorst J, ter Laak AM, Commandeur JN, Funae Y, Hiroi T, Vermeulen NP.
Abstract : The ligand-binding characteristics of rat and human CYP2D isoforms, i.e., rat CYP2D1-4 and human CYP2D6, were investigated by measuring IC(50) values of 11 known CYP2D6 ligands using 7-methoxy-4-(aminomethyl)coumarin (MAMC) as substrate. Like CYP2D6, all rat CYP2D isozymes catalyzed the O-demethylation of MAMC with K(m) and V(max) values ranging between 78 and 145 microM and 0.048 and 1.122 min(-1), respectively. To rationalize observed differences in the experimentally determined IC(50) values, homology models of the CYP2D isoforms were constructed. A homology model of CYP2D6 was generated on the basis of crystallized rabbit CYP2C5 and was validated on its ability to reproduce binding orientations corresponding to metabolic profiles of the substrates and to remain stable during unrestrained molecular dynamics simulations at 300 K. Twenty-two active site residues, sharing up to 59% sequence identity, were identified in the CYP2D binding pockets and included CYP2D6 residues Phe120, Glu216, and Asp301. Electrostatic potential calculations displayed large differences in the negative charge of the CYP2D active sites, which was consistent with observed differences in absolute IC(50) values. MD studies on the binding mode of sparteine, quinidine, and quinine in CYP2D2 and CYP2D6 furthermore concurred well with experimentally determined IC(50) values and metabolic profiles. The current study thus provides new insights into differences in the active site topology of the investigated CYP2D isoforms.
|
Parasympatholytic activity and the % inhibition of guinea pig ileum contractile force at 4 mg/L of base was reported.
|
Cavia porcellus
|
62.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 3. Modifications to the linkage region (region 3).
Year : 1985
Volume : 28
Issue : 3
First Page : 295
Last Page : 298
Authors : Stout DM, Matier WL, Barcelon-Yang C, Reynolds RD, Brown BS.
Abstract : As part of a continuing program of systematically modifying the structure of the class I antiarrhythmic drug changrolin, we synthesized 15 analogues in which the linkage between the two aromatic regions was altered. High antiarrhythmic activity and low parasympatholytic activity was found when the linkage region, designated region 3, contained a carbonyl moiety, including ketones, amides, and ureas. Secondary amides were superior to tertiary amides, while amide reversal resulted in no change in activities. One compound in this series, 7, 2,6-bis(1-pyrrolidinyl-methyl)-4-benzamidophenol (ACC-9358), is undergoing preclinical evaluations.
|
Parasympatholytic activity was assessed from the ability to inhibit electrically stimulated contraction of isolated guinea pig ileum at 4 mg/L of base
|
Cavia porcellus
|
62.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 2. Amides.
Year : 1984
Volume : 27
Issue : 10
First Page : 1347
Last Page : 1350
Authors : Stout DM, Matier WL, Barcelon-Yang C, Reynolds RD, Brown BS.
Abstract : Thirty amides patterned after the antiarrhythmic drug changrolin were synthesized and their antiarrhythmic and parasympatholytic activities were assessed. There was no correlation between antiarrhythmic and parasympatholytic activities. Several of the amides were found to be potent antiarrhythmic agents that possessed low parasympatholytic activity. All of the compounds appear to act by a class I mechanism.
|
Inhibition of 1'-hydroxybufuralol formation by human liver microsomes
|
Homo sapiens
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibitory effect on Bufuralol 1'-hydroxylation by human liver microsomes (Ki = apparent inhibition constant)
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
The compound was tested for effective concentration (intradermal injection) that caused local anesthesia in 50% of mice by tail-clip method
|
Mus musculus
|
0.0098
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiarrhythmic activity of new 3-[2-(omega-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds.
Year : 1987
Volume : 30
Issue : 5
First Page : 773
Last Page : 780
Authors : Salimbeni A, Manghisi E, Fregnan GB, Prada M.
Abstract : A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.
|
Inhibition of partially purified cytochrome P450 2D6 1'-hydroxybufuralol formation
|
Homo sapiens
|
43.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibitory constant for cytochrome P450 2D6
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies.
Year : 1993
Volume : 36
Issue : 9
First Page : 1136
Last Page : 1145
Authors : Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, Wolff T.
Abstract : To gain insight into the specificity of cytochrome P-450 2D6 toward inhibitors, a preliminary pharmacophore model was built up using strong competitive inhibitors. Ajmalicine (1), the strongest inhibitor known (Ki = 3 nM) was selected as template because of its rigid structure. The preliminary pharmacophore model was validated by performing inhibition studies with derivatives of ajmalicine (1) and quinidine (9). Bufuralol (18) was chosen as substrate and the metabolite 1'-hydroxybufuralol (19) was separated by high performance liquid chromatography. All incubations were carried out using human liver microsomes after demonstration that the Ki values obtained with microsomes were in accordance with those obtained with a reconstituted monooxygenase system containing purified cytochrome P-450 2D6. Large differences of Ki values ranging between 0.005 and 100 microM were observed. Low-energy conformers of tested compounds were fit within the preliminary pharmacophore model. The analysis of steric and electronic properties of these compounds led to the definition of a final pharmacophore model. Characteristic properties are a positive charge on a nitrogen atom and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5 A and 6.6-7.5 A from the nitrogen atom. The superposition of strong and weak inhibitors led to the definition of an excluded volume map. Compounds that required additional space were not inhibitors. This is apparently the first pharmacophore model for inhibitors of a cytochrome P-450 enzyme and offers the opportunity to classify compounds according to their potency of inhibition. Adverse drug interactions which occur when both substrates and inhibitors of cytochrome P-450 2D6 are applied may be predicted.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
In vitro antimalarial activity against Plasmodium falciparum W2 in human erythrocytes by [3H]hypoxanthine uptake
|
Plasmodium falciparum
|
160.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of new antimalarial analogues of quinoline alkaloids derived from Cinchona ledgeriana Moens ex Trimen.
Year : 2002
Volume : 12
Issue : 10
First Page : 1351
Last Page : 1355
Authors : Park BS, Kim DY, Rosenthal PJ, Huh SC, Lee BJ, Park E-, Kim SM, Kim JE, Kim MH, Huh TL, Choi YJ, Suh KH, Choi WS, Lee SE.
Abstract : In the course of attempts to develop antimalarial drugs, we have designed and synthesized a series of quinoline alkaloide derivatives. Three of them, N-(4-methoxy-3,5-di-tert-butylbenzyl)cinchonidinium bromide (OSL-5), O-benzyl-N-(3,5-di-tert-butyl-4-methoxybenzyl)cinchonidinium bromide (OSL-7), and N-(3,5-di-tert-butyl-4-methoxybenzyl)quininium bromide (OSL-14) show potent activity against Plasmodium falciparum.
|
In vitro inhibition of parasite development of Plasmodium falciparum W2 in human erythrocytes
|
Plasmodium falciparum
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of new antimalarial analogues of quinoline alkaloids derived from Cinchona ledgeriana Moens ex Trimen.
Year : 2002
Volume : 12
Issue : 10
First Page : 1351
Last Page : 1355
Authors : Park BS, Kim DY, Rosenthal PJ, Huh SC, Lee BJ, Park E-, Kim SM, Kim JE, Kim MH, Huh TL, Choi YJ, Suh KH, Choi WS, Lee SE.
Abstract : In the course of attempts to develop antimalarial drugs, we have designed and synthesized a series of quinoline alkaloide derivatives. Three of them, N-(4-methoxy-3,5-di-tert-butylbenzyl)cinchonidinium bromide (OSL-5), O-benzyl-N-(3,5-di-tert-butyl-4-methoxybenzyl)cinchonidinium bromide (OSL-7), and N-(3,5-di-tert-butyl-4-methoxybenzyl)quininium bromide (OSL-14) show potent activity against Plasmodium falciparum.
|
Percentage inhibition of specific binding of [3H]dofetilide (UK-68,798) from cardiac myocytes with blockade of delayed rectifier K+ channel
|
Cavia porcellus
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : 4,5-Dihydro-1-phenyl-1H-2,4-benzodiazepines: novel antiarrhythmic agents.
Year : 1993
Volume : 36
Issue : 22
First Page : 3361
Last Page : 3370
Authors : Johnson RE, Baizman ER, Becker C, Bohnet EA, Bell RH, Birsner NC, Busacca CA, Carabateas PM, Chadwick CC, Gruett MD.
Abstract : A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 microM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for ventricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.
|
Inhibition of human Potassium channel HERG expressed in mammalian cells
|
Homo sapiens
|
323.59
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods.
Year : 2003
Volume : 13
Issue : 16
First Page : 2773
Last Page : 2775
Authors : Keserü GM.
Abstract : Traditional and hologram QSAR (HQSAR) models were developed for the prediction of hERG potassium channel affinities. The models were validated on three different test sets including compounds with published patch-clamp IC(50) data and two subsets from the World Drug Index (compounds indicated to have ECG modifying adverse effect and drugs marked to be approved, respectively). Discriminant analysis performed on the full set of hERG data resulted in a traditional QSAR model that classified 83% of actives and 87% of inactives correctly. Analysis of our HQSAR model revealed it to be predictive in both IC(50) and discrimination studies.
|
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
|
74.1
%
|
|
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.
|
Percentage inhibition of specific binding of [3H]batrachotoxin [3H]BTX) in sodium channel from cardiac myocytes at 10 uM
|
Rattus norvegicus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : 4,5-Dihydro-1-phenyl-1H-2,4-benzodiazepines: novel antiarrhythmic agents.
Year : 1993
Volume : 36
Issue : 22
First Page : 3361
Last Page : 3370
Authors : Johnson RE, Baizman ER, Becker C, Bohnet EA, Bell RH, Birsner NC, Busacca CA, Carabateas PM, Chadwick CC, Gruett MD.
Abstract : A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory period (ERP) in anesthetized guinea pigs. Concomitant displacement of radiolabeled bactrachotoxin from site II in Na+ channels and of radiolabeled dofetilide from delayed rectifier K+ channels was evident with all members of this chemical series at a concentration of 10 microM. Structure-activity relationship (SAR) studies using a paced guinea pig model to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caused a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more potent; however, too many lipophilic substituents simultaneously at positions 1, 3, and 4 resulted in less active compounds. Substituents on either aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic activity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this series increased the threshold for ventricular fibrillation and refractoriness in myocardially-infarcted anesthetized cata and delayed the onset of aconitine-induced arrhythmias in anesthetized guinea pigs following intravenous dosing. Moreover, these compounds possessed oral antiarrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evaluations.
|
Binding affinity for cytochrome P450 2D6
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition.
Year : 2004
Volume : 47
Issue : 22
First Page : 5340
Last Page : 5346
Authors : Kemp CA, Flanagan JU, van Eldik AJ, Maréchal JD, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ.
Abstract : There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.
|
Inhibitory concentration against cytochrome P450 2D6
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition.
Year : 2004
Volume : 47
Issue : 22
First Page : 5340
Last Page : 5346
Authors : Kemp CA, Flanagan JU, van Eldik AJ, Maréchal JD, Wolf CR, Roberts GC, Paine MJ, Sutcliffe MJ.
Abstract : There has been much interest in the development of a predictive model of cytochrome P450 2D6 particularly because this enzyme is involved in the oxidation of at least 50 drugs. Previously we have described the combined use of homology modeling and molecular docking to correctly position a range of substrates in the CYP2D6 active site with the known sites of metabolism above the heme. Here, our approach identifies correctly the site of metabolism of the atypical (no basic nitrogen) cytochrome P450 2D6 substrate, spirosulfonamide. The same method is used to screen a small compound database for cytochrome P450 2D6 inhibition. A database containing 33 compounds from the National Cancer Institute database was docked into our cytochrome P450 2D6 homology model using the program GOLDv2.0. Experimental IC50 values for the 33 compounds were determined; comparison with the corresponding docked scores revealed a correlation with a regression coefficient of r2 = 0.61 (q2 = 0.59). The method was able to discriminate between tight and weak binding compounds and correctly identified several novel inhibitors. The results therefore suggest that our approach, which combines homology modeling with molecular docking, has produced a useful predictive in silico tool for cytochrome P450 2D6 inhibition, which is best used as one filter in a multifilter database screen.
|
Inhibitory concentration against potassium channel HERG
|
None
|
323.59
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors.
Year : 2005
Volume : 15
Issue : 11
First Page : 2886
Last Page : 2890
Authors : Tobita M, Nishikawa T, Nagashima R.
Abstract : HERG attracts attention as a risk factor for arrhythmia, which might trigger torsade de pointes. A highly accurate classifier of chemical compounds for inhibition of the HERG potassium channel is constructed using support vector machine. For two test sets, our discriminant models achieved 90% and 95% accuracy, respectively. The classifier is even applied for the prediction of cardio vascular adverse effects to achieve about 70% accuracy. While modest inhibitors are partly characterized by properties linked to global structure of a molecule including hydrophobicity and diameter, strong inhibitors are exclusively characterized by properties linked to substructures of a molecule.
|
Inhibition of human CYP2D6
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis.
Year : 2006
Volume : 49
Issue : 7
First Page : 2222
Last Page : 2231
Authors : Voets M, Antes I, Scherer C, Müller-Vieira U, Biemel K, Marchais-Oberwinkler S, Hartmann RW.
Abstract : In this study, the synthesis and biological evaluation of heteroaryl-substituted dihydronaphthalenes and indenes (1-16) is described. The compounds were tested for activity by use of human CYP11B2 expressed in fission yeast and V79 MZh cells and for selectivity by use of human CYP11B1, CYP17, and CYP19. The most active inhibitor was the 6-methoxydihydronaphthalene 4 (IC(50) = 2 nM), showing a K(i) value of 1.3 nM and a competitive type of inhibition. The 5-methoxyindene 3 was found to be the most selective CYP11B2 inhibitor (IC(50) = 4 nM; CYP11B1 IC(50) = 5684 nM), which also showed only marginal inhibition of human CYP3A4 and CYP2D6. Docking and molecular dynamics studies using our homology-modeled CYP11B2 structure were performed to understand some structure-activity relationships. Caco-2 cell experiments revealed highly cell-permeable compounds, and metabolic studies with 4 using rat liver microsomes showed sufficient stability.
|
Inhibition of calcium-induced contraction of potassium ion depolarized guinea pig aortic strips at 100 uM
|
Cavia porcellus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Novel quinolizidinyl derivatives as antiarrhythmic agents.
Year : 2007
Volume : 50
Issue : 2
First Page : 334
Last Page : 343
Authors : Vazzana I, Budriesi R, Terranova E, Ioan P, Ugenti MP, Tasso B, Chiarini A, Sparatore F.
Abstract : Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.
|
Inhibition of CYP2D6 in human liver microsomes
|
Homo sapiens
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.
Year : 2007
Volume : 50
Issue : 4
First Page : 807
Last Page : 819
Authors : Liverton NJ, Bednar RA, Bednar B, Butcher JW, Claiborne CF, Claremon DA, Cunningham M, DiLella AG, Gaul SL, Libby BE, Lyle EA, Lynch JJ, McCauley JA, Mosser SD, Nguyen KT, Stump GL, Sun H, Wang H, Yergey J, Koblan KS.
Abstract : The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
|
Inhibition of human CYP2D6
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.
Year : 2008
Volume : 51
Issue : 7
First Page : 2158
Last Page : 2169
Authors : Frotscher M, Ziegler E, Marchais-Oberwinkler S, Kruchten P, Neugebauer A, Fetzer L, Scherer C, Müller-Vieira U, Messinger J, Thole H, Hartmann RW.
Abstract : Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.
|
Inhibition of human recombinant CYP2D6 expressed in insect microsomes
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity.
Year : 2008
Volume : 51
Issue : 16
First Page : 5064
Last Page : 5074
Authors : Heim R, Lucas S, Grombein CM, Ries C, Schewe KE, Negri M, Müller-Vieira U, Birk B, Hartmann RW.
Abstract : Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 microM concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.
|
Inhibition of human recombinant CYP2D6 expressed in baculovirus-infected insect microsomes
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach.
Year : 2008
Volume : 51
Issue : 19
First Page : 6138
Last Page : 6149
Authors : Lucas S, Heim R, Negri M, Antes I, Ries C, Schewe KE, Bisi A, Gobbi S, Hartmann RW.
Abstract : Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.
|
Inhibition of human CYP2D6 expressed in baculovirus-infected insect cell system
|
Homo sapiens
|
19.6
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts.
Year : 2009
Volume : 52
Issue : 3
First Page : 626
Last Page : 636
Authors : Ponte-Sucre A, Gulder T, Wegehaupt A, Albert C, Rikanović C, Schaeflein L, Frank A, Schultheis M, Unger M, Holzgrabe U, Bringmann G, Moll H.
Abstract : Alternative drugs against leishmaniasis are desperately needed. Antimonials, the main chemotherapeutic tool, cause serious side effects and promote chemoresistance. We previously demonstrated that representatives of N,C-linked arylisoquinolines are promising leishmanicidal drug candidates. We now performed structure-activity relationship studies varying the aryl portion of our lead substrate. The new series of compounds show an enhanced selectivity against Leishmania major in comparison to their major host cell, the macrophage. Our results suggest that the arylisoquinolinium salts decrease the macrophage infection rate acting directly on the intracellular parasites. However, the activity of the 4'-i-propyl derivative might also involve the modulation of cytokine and nitric oxide production by host macrophages. Additionally, this isoquinoline acts synergistically with amphotericin B and does not interact with drug-metabolizing cytochrome P450 enzymes involved in the metabolism of antileishmanial drugs. The results demonstrate that the newly synthesized structurally simplified N,C-coupled arylisoquinolinium salts are promising candidates to be considered as leishmanicidal pharmacophores.
|
Inhibition of human CYP2D6 by Lineweaver-Burke plot
|
Homo sapiens
|
9.8
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts.
Year : 2009
Volume : 52
Issue : 3
First Page : 626
Last Page : 636
Authors : Ponte-Sucre A, Gulder T, Wegehaupt A, Albert C, Rikanović C, Schaeflein L, Frank A, Schultheis M, Unger M, Holzgrabe U, Bringmann G, Moll H.
Abstract : Alternative drugs against leishmaniasis are desperately needed. Antimonials, the main chemotherapeutic tool, cause serious side effects and promote chemoresistance. We previously demonstrated that representatives of N,C-linked arylisoquinolines are promising leishmanicidal drug candidates. We now performed structure-activity relationship studies varying the aryl portion of our lead substrate. The new series of compounds show an enhanced selectivity against Leishmania major in comparison to their major host cell, the macrophage. Our results suggest that the arylisoquinolinium salts decrease the macrophage infection rate acting directly on the intracellular parasites. However, the activity of the 4'-i-propyl derivative might also involve the modulation of cytokine and nitric oxide production by host macrophages. Additionally, this isoquinoline acts synergistically with amphotericin B and does not interact with drug-metabolizing cytochrome P450 enzymes involved in the metabolism of antileishmanial drugs. The results demonstrate that the newly synthesized structurally simplified N,C-coupled arylisoquinolinium salts are promising candidates to be considered as leishmanicidal pharmacophores.
|
Inhibition of human liver microsome CYP2D6 in assessed as [14C]formaldehyde formation
|
Homo sapiens
|
82.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potent CYP3A4 inhibitory constituents of Piper cubeba.
Year : 2005
Volume : 68
Issue : 1
First Page : 64
Last Page : 68
Authors : Usia T, Watabe T, Kadota S, Tezuka Y.
Abstract : The EtOAc-soluble fraction of the water extract of Piper cubeba, having shown potent inhibitory activity on the metabolism mediated by CYP3A4, was subjected to activity-guided isolation to yield two new lignans, (8R,8'R)-4-hydroxycubebinone (1) and (8R,8'R,9'S)-5-methoxyclusin (2), and two new sesquiterpenes, (5 alpha,8 alpha)-2-oxo-1(10),3,7(11)-guaiatrien-12,8-olide (3) and (1 alpha,2 beta,5 alpha,8 alpha 10 alpha)-1,10-epoxy-2-hydroxy-3,7(11)-guaiadien-12,8-olide (4), along with 16 known compounds (5-20). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. The compounds (8R,8'R,9'S)-5-methoxyclusin (2), (-)-clusin (10), (-)-yatein (13), ethoxyclusin (15), and (-)-dihydroclusin (17), having one methylenedioxyphenyl moiety in their structures, showed very potent and selective inhibitory activity against CYP3A4 with IC(50) values (0.44-1.0 microM) identical to that of the positive control, ketoconazole (IC(50), 0.72 microM).
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
62.9
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Cardiotoxicity in iv dosed Dunkin-Hartley guinea pig assessed as drug level required to evoke 50 ms QTc prolongation administered as 3 fold cumulative doses measured every 10 seconds at end of every 20 mins follow up period of individual dose by ECG
|
Cavia porcellus
|
8.34
umol/Kg
|
|
Journal : Eur. J. Med. Chem.
Title : Identification of "toxicophoric" features for predicting drug-induced QT interval prolongation.
Year : 2008
Volume : 43
Issue : 11
First Page : 2479
Last Page : 2488
Authors : Coi A, Massarelli I, Testai L, Calderone V, Bianucci AM.
Abstract : Drugs delaying cardiac repolarization by blockade of hERG K(+) channel generally prolong the QT interval of the electrocardiogram, an effect regarded as a cardiac risk factor with the potential to cause 'torsade des pointes'-type arrhythmias in humans. The present study applied a homology building technique and molecular dynamics simulations to model the pore of hERG K(+) channel. A docking analysis was then performed on selected ligands which were classified as QT-prolonging or non-prolonging after experimental measurements in in vivo anesthetized guinea pig. The results of this structural analysis provided a "toxicophoric" model that was further exploited to inspect a dataset of known QT-prolonging/non-prolonging molecules. The emerging major chemical features to be avoided, in order to obtain cardiac safe therapeutic agents, comprise the simultaneous presence of (i) a protonated nitrogen atom within an observed range of distances from a heteroatom; (ii) aromatic groups capable of interacting within an area defined by Gly657 residues of the pore or within an area located at the top of the longitudinal axis of the pore. Moreover, additional hydrophobic moieties interacting with one of the equatorial cavities located in the area near-by Tyr652 residues and/or with a hydrophobic ring defined by Phe656 residues should be avoided.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 after 48 hrs by [G-3H]hypoxanthine uptake
|
Plasmodium falciparum K1
|
51.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Pharmacophore based discovery of potential antimalarial agent targeting haem detoxification pathway.
Year : 2008
Volume : 43
Issue : 12
First Page : 2840
Last Page : 2852
Authors : Acharya BN, Saraswat D, Kaushik MP.
Abstract : Pharmacophore hypotheses were generated from molecules having putative antimalarial activities targeting haem detoxification pathway of malarial parasite. A training set consisting of 33 compounds, whose activities were evaluated for haem polymerization inhibition and against chloroquine resistant (K1) strain of Plasmodium falciparum, was optimized to generate hypotheses. The hypothesis showing optimum correlation between actual and estimated activities was validated by Fischer's randomization test at 95% confidence level and used as a model to screen our in-house compound database. Nicotinic acid [trans-3-(4-ethoxy-3-methoxy-phenyl)-1-(4-hydroxy-phenyl)-allylidene]-hydrazide (ALH5) was obtained as a hit. The compound was synthesized and evaluated against chloroquine sensitive (MRC-02) and resistant (RKL9) strains of malarial parasite P. falciparum. The compound showed antimalarial activity in nanomolar range and was found comparable with chloroquine.
|
Inhibition of human CYP2D6 by radiometric assay
|
Homo sapiens
|
78.0
nM
|
|
Journal : J. Nat. Prod.
Title : Sesquiterpenes and flavonol glycosides from Zingiber aromaticum and their CYP3A4 and CYP2D6 inhibitory activities.
Year : 2004
Volume : 67
Issue : 7
First Page : 1079
Last Page : 1083
Authors : Usia T, Iwata H, Hiratsuka A, Watabe T, Kadota S, Tezuka Y.
Abstract : Three new sesquiterpenes, (2R,3S,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (1), (2R,3R,5R)-2,3-epoxy-6,9-humuladien-5-ol-8-one (2), and (5R)-2,6,9-humulatrien-5-ol-8-one (3), and two new flavonol glycosides, kaempferol-3-O-(2,3-di-O-acetyl-alpha-l-rhamnopyranoside) (4) and kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5), were isolated from the EtOAc-soluble fraction of the water extract of Zingiber aromaticum, along with 13 known compounds (6-18). The structures of the isolated compounds were elucidated on the basis of spectroscopic and chemical analyses. The isolated compounds were tested for their inhibitory activity on the metabolism mediated by CYP3A4 or CYP2D6 using [N-methyl-(14)C]erythromycin or [O-methyl-(14)C]dextromethorphan as a substrate, respectively. Kaempferol-3-O-(2,3,4-tri-O-acetyl-alpha-l-rhamnopyranoside) (5) showed the most potent inhibitory activity (IC(50), 14.4 microM) on the metabolism mediated by CYP3A4, and kaempferol-3-O-methyl ether (14) inhibited CYP2D6 most potently (IC(50), 4.63 microM).
|
Inhibition of human ERG expressed in CHO cells by whole cell patch clamp technique
|
Homo sapiens
|
323.59
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Support vector machines classification of hERG liabilities based on atom types.
Year : 2008
Volume : 16
Issue : 11
First Page : 6252
Last Page : 6260
Authors : Jia L, Sun H.
Abstract : Drug-induced long QT syndrome (LQTS) can cause critical cardiovascular side effects and has accounted for the withdrawal of several drugs from the market. Blockade of the potassium ion channel encoded by the human ether-a-go-go-related gene (hERG) has been identified as a major contributor to drug-induced LQTS. Experimental measurement of hERG activity for each compound in development is costly and time-consuming, thus it is beneficial to develop a predictive hERG model. Here, we present a hERG classification model formulated using support vector machines (SVM) as machine learning method and using atom types as molecular descriptors. The training set used in this study was composed of 977 corporate compounds with hERG activities measured under the same conditions. The impact of soft margin and kernel function on the performance of the SVM models was examined. The robustness of SVM was evaluated by comparing the predictive power of the models built with 90%, 50%, and 10% of the training set data. The final SVM model was able to correctly classify 94% of an external testing set containing 66 drug molecules. The most important atom types with respect to discriminative power were extracted and analyzed.
|
Inhibition of human recombinant CYP2D6 at 5 uM assessed as blockade of O-demethylation of dextromethorphan in to dextrophan by nanoscale automated in-capillary assay
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Development of an in-capillary approach to nanoscale automated in vitro cytochromes p450 assays.
Year : 2009
Volume : 52
Issue : 8
First Page : 2192
Last Page : 2195
Authors : Nicoli R, Curcio R, Rudaz S, Veuthey JL.
Abstract : A method to perform nanoscale automated CYP450-based drug metabolism studies using a capillary as a reaction vessel is described. In-capillary assays consumed only approximately 30 nL of recombinant human CYP450 solution. Ultrafast analysis of substrates and metabolites was achieved off-line by ultrahigh-pressure liquid chromatography coupled to mass spectrometry. This approach was successfully applied to qualitative metabolism studies of six major CYP450 isozymes and CYP2D6 inhibition experiments.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
98.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum Dd2 in whole red blood cells, using parasite LDH activity as an index of growth. Test compounds present at 2uM
|
Plasmodium falciparum
|
95.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Inhibition of Plasmodium falciparum 3D7 LDH activity, using an LDH reporter assay. Test compounds present at 2uM
|
Plasmodium falciparum
|
0.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
GSK_TCMDC: Percent inhibition of human HepG2 cell line. Test compounds present at 10uM.
|
Homo sapiens
|
0.0
%
|
|
Journal : Nature
Title : Thousands of chemical starting points for antimalarial lead identification.
Year : 2010
Volume : 465
Issue : 7296
First Page : 305
Last Page : 310
Authors : Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF.
Abstract : Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 microM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host-pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification efforts and further research into this disease.
|
NOVARTIS: Inhibition of Plasmodium falciparum 3D7 (drug-susceptible) proliferation in erythrocyte-based infection assay
|
Plasmodium falciparum
|
9.59
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
Year : 2008
Volume : 105
Issue : 26
First Page : 9059
Last Page : 9064
Authors : Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P, Nam TG, Gray NS, Chatterjee A, Janes J, Yan SF, Trager R, Caldwell JS, Schultz PG, Zhou Y, Winzeler EA.
Abstract : The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
|
NOVARTIS: Inhibition of Plasmodium falciparum W2 (drug-resistant) proliferation in erythrocyte-based infection assay
|
Plasmodium falciparum
|
35.2
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen.
Year : 2008
Volume : 105
Issue : 26
First Page : 9059
Last Page : 9064
Authors : Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P, Nam TG, Gray NS, Chatterjee A, Janes J, Yan SF, Trager R, Caldwell JS, Schultz PG, Zhou Y, Winzeler EA.
Abstract : The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.
|
Vasorelaxant activity in potassium depolarized guinea pig aortic strip assessed as inhibition of calcium-induced contraction at 50 uM
|
Cavia porcellus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Novel quinolizidinyl derivatives as antiarrhythmic agents: 2. Further investigation.
Year : 2010
Volume : 53
Issue : 12
First Page : 4668
Last Page : 4677
Authors : Tasso B, Budriesi R, Vazzana I, Ioan P, Micucci M, Novelli F, Tonelli M, Sparatore A, Chiarini A, Sparatore F.
Abstract : Fifteen quinolizidine derivatives have been tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. All compounds exhibited from moderate to high antiarrhythmic activity, and five of them (3, 4, 6, 13, and 15) were more active and potent than the reference drugs (amiodarone, lidocaine, procainamide, and quinidine). These compounds were studied on spontaneously beating Langendorff-perfuse gp heart; even at concentration 17-67 times higher than the corresponding EC(50) for antiarrhythmic activity, they prolonged the QT intervals only moderately, comparing favorably with amiodarone and quinidine. Compounds 3 and 15 deserve further investigation due to their interesting cardiovascular profiles.
|
Inhibition of human CYP2D6
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.
Year : 2011
Volume : 54
Issue : 2
First Page : 534
Last Page : 547
Authors : Marchais-Oberwinkler S, Wetzel M, Ziegler E, Kruchten P, Werth R, Henn C, Hartmann RW, Frotscher M.
Abstract : Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17β-HSD1 inhibitors from the hydroxyphenylnaphthol class, structural optimizations were performed at the 1-position of the naphthalene by introduction of different heteroaromatic rings as well as substituted phenyl groups. In the latter class of compounds, which were synthesized applying Suzuki-cross coupling, the 3-methanesulfonamide 15 turned out to be a highly potent 17β-HSD1 inhibitor (IC(50) = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC(50) = 71 nM) and selective toward 17β-HSD2 and the estrogen receptors α and β. It showed a good membrane permeation and metabolic stability and was orally available in the rat.
|
Inhibition of CYP2D6 after 30 mins by fluorometric assay
|
None
|
10.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cytochrome P450 3A4 inhibitory constituents of the wood of Taxus yunnanensis.
Year : 2011
Volume : 74
Issue : 1
First Page : 102
Last Page : 105
Authors : Tezuka Y, Morikawa K, Li F, Auw L, Awale S, Nobukawa T, Kadota S.
Abstract : From the aqueous extract of the wood of Taxus yunnanensis, which showed cytochrome P450 3A4 (CYP3A4) inhibition, a new isoflavan [(3S,4R)-4'-hydroxy-6,3'-dimethoxyisoflavan-4-ol (1)], a new degraded lignan [2,3-bis(hydroxymethyl)-7-hydroxy-6-methoxy-1-tetralone (2)], and a new lignan [(7R)-7-hydroxytaxiresinol (3)] were isolated, together with nine known lignans. Among the isolates obtained, α-conidendrin (12) showed strong CYP3A4 inhibition with an IC(50) value of 0.2 μM.
|
Inhibition of human CYP2D6 expressed in baculovirus-infected insect microsomes
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives.
Year : 2011
Volume : 54
Issue : 7
First Page : 2307
Last Page : 2319
Authors : Lucas S, Negri M, Heim R, Zimmer C, Hartmann RW.
Abstract : Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11β-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome.
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 20 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
85.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Antimalarial activity against chloroquine sensitive Plasmodium falciparum HB3 after 72 hrs by SYBP Green I dye staining
|
Plasmodium falciparum HB3
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.
Year : 2012
Volume : 20
Issue : 10
First Page : 3292
Last Page : 3297
Authors : Dinio T, Gorka AP, McGinniss A, Roepe PD, Morgan JB.
Abstract : Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN.
|
Antimalarial activity against chloroquine resistant Plasmodium falciparum Dd2 after 72 hrs by SYBP Green I dye staining
|
Plasmodium falciparum
|
90.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum.
Year : 2012
Volume : 20
Issue : 10
First Page : 3292
Last Page : 3297
Authors : Dinio T, Gorka AP, McGinniss A, Roepe PD, Morgan JB.
Abstract : Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN.
|
Inhibition of norA-mediated ethidium bromide efflux in Staphylococcus aureus SA-1199B harboring grlA A116E mutant at 50 uM after 5 mins by fluorometric analysis
|
Staphylococcus aureus
|
31.5
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA.
Year : 2012
Volume : 3
Issue : 3
First Page : 248
Last Page : 251
Authors : Brincat JP, Broccatelli F, Sabatini S, Frosini M, Neri A, Kaatz GW, Cruciani G, Carosati E.
Abstract : Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.
|
Inhibition of human recombinant MDR1 expressed in mouse L5178Y cells assessed as inhibition of rhodamine-123 efflux at 10'-4 M preincubated for 10 mins measured after 20 mins by FACS analysis
|
Homo sapiens
|
21.1
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA.
Year : 2012
Volume : 3
Issue : 3
First Page : 248
Last Page : 251
Authors : Brincat JP, Broccatelli F, Sabatini S, Frosini M, Neri A, Kaatz GW, Cruciani G, Carosati E.
Abstract : Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while seven compounds inhibited only NorA. These results demonstrate that Pgp and NorA inhibitors do not necessarily overlap, opening the way to safer therapeutic use of effective NorA inhibitors.
|
TP_TRANSPORTER: transepithelial transport of digoxin (basal to apical) in Caco-2 cells
|
None
|
430.0
nM
|
|
Journal : Pharm. Res.
Title : Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance protein efflux transporter.
Year : 2003
Volume : 20
Issue : 1
First Page : 161
Last Page : 168
Authors : Horie K, Tang F, Borchardt RT.
Abstract : PURPOSE: The purpose of this study was to isolate Caco-2 subclones that express high levels of multidrug resistance protein (MDR1) and to characterize their kinetics and affinity parameters for MDR1 substrate/inhibitors. METHODS: The subclones were selected by a dilution cloning technique. The polarized efflux of [3H]-vinblastine across subclone cell monolayers was quantified by measuring the apparent permeability coefficients (Papp) of [3H]-vinblastine in the basolateral (BL)-to-apical (AP) direction and in the AP-to-BL direction (Papp BL-to-AP/Papp AP-to-BL) across the cell monolayers. The expression of MDR1 in the Caco-2 subclones compared with the parental Caco-2 cells was confirmed by Western blotting analysis. The kinetics parameters (Km, Vmax) of [3H]-vinblastine and the inhibitory constants (KI) of several known MDR1 substrates/inhibitors on the transport of [3H]-digoxin determined in the parental Caco-2 cells and Caco-2 subclones were also compared. RESULTS: Three subclones (#1, #20, #21) were selected based on their polarized efflux of [3H]-vinblastine. The Papp BL-to-AP/Papp AP-to-BL ratios for #1, #20, and #21 were 110, 140, and 112, respectively, and were about 6-fold higher than the ratio observed for the parental Caco-2 cells. In the presence of GF-120918 (2 microM), a known MDR1-specific inhibitor, the Papp BL-to-AP/Papp AP-to-BL ratios were significantly decreased, suggesting that these cells were overexpressing MDRI. The Km values observed for vinblastine in the Caco-2 subclones were nearly identical to the value observed in the parental Caco-2 cells. In contrast, the Vmax values observed in the subclones were approximate 26-69% higher. The KI values observed for various known MDR1 substrates/inhibitors on [3H]-digoxin transport were nearly identical to those in the parental Caco-2 cells and Caco-2 subclones. The high functional efflux activities of these subclones were stable up to 6 months. CONCLUSIONS: Subclones #1, #20, #21 express high levels of MDR1. These Caco-2 subclones may be useful models for profiling drugs for their MDR1 substrate activity and for establishing structure-transport relationships for this efflux transporter.
|
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
|
43.3
%
|
|
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
|
37.2
%
|
|
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 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
|
-10.0
%
|
|
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.
|
Antimalarial activity against chloroquine-resistant Plasmodium falciparum K1 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum K1
|
51.0
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
|
Antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 assessed as incorporation of [3H]hypoxanthine after 48 hr microdilution method
|
Plasmodium falciparum 3D7
|
21.0
nM
|
|
Journal : Med Chem Res
Title : Pharmacophore-based predictive model generation for potent antimalarials targeting haem detoxification pathway
Year : 2007
Volume : 16
Issue : 5
First Page : 213
Last Page : 229
Authors : Acharya BN, Kaushik MP
|
Antiamoebic activity against Entamoeba histolytica
|
Entamoeba histolytica
|
16.6
ug.mL-1
|
|
Journal : Med Chem Res
Title : Exploring QSAR of antiamoebic agents of isolated natural products by MLR, ANN, and RTO
Year : 2012
Volume : 21
Issue : 9
First Page : 2501
Last Page : 2516
Authors : Ramirez-Galicia G, Martinez-Pacheco H, Garduno-Juarez R, Deeb O
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
28.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Antiplasmodial activity against erythrocytic stage of chloroquine-sensitive Plasmodium falciparum 3D7 assessed as parasite LDH activity by three-fold serial dilution method
|
Plasmodium falciparum
|
0.06
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiparasitic hybrids of Cinchona alkaloids and bile acids.
Year : 2013
Volume : 66
First Page : 355
Last Page : 363
Authors : Leverrier A, Bero J, Frédérich M, Quetin-Leclercq J, Palermo J.
Abstract : A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC₅₀ values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC₅₀ ≤ 6 μg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC₅₀ values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
|
Antileishmanial activity against Leishmania mexicana mexicana MHOM/BZ/84/BEL46 promastigotes assessed as parasite LDH activity by three-fold serial dilution method
|
Leishmania mexicana mexicana
|
20.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiparasitic hybrids of Cinchona alkaloids and bile acids.
Year : 2013
Volume : 66
First Page : 355
Last Page : 363
Authors : Leverrier A, Bero J, Frédérich M, Quetin-Leclercq J, Palermo J.
Abstract : A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC₅₀ values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC₅₀ ≤ 6 μg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC₅₀ values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
|
Antitrypanosomal activity against Trypanosoma brucei brucei Lister 427 bloodstream form assessed as parasite LDH activity by three-fold serial dilution method
|
Trypanosoma brucei brucei
|
8.42
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiparasitic hybrids of Cinchona alkaloids and bile acids.
Year : 2013
Volume : 66
First Page : 355
Last Page : 363
Authors : Leverrier A, Bero J, Frédérich M, Quetin-Leclercq J, Palermo J.
Abstract : A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC₅₀ values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC₅₀ ≤ 6 μg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC₅₀ values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
|
Cytotoxicity against human WI38 cells by MTT assay
|
Homo sapiens
|
11.28
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Antiparasitic hybrids of Cinchona alkaloids and bile acids.
Year : 2013
Volume : 66
First Page : 355
Last Page : 363
Authors : Leverrier A, Bero J, Frédérich M, Quetin-Leclercq J, Palermo J.
Abstract : A series of 16 hybrids of Cinchona alkaloids and bile acids (4a-h, 5a-h) was prepared by means of a Barton-Zard decarboxylation reaction. Quinine, quinidine, cinchonine and cinchonidine were functionalized at position C-2 of the quinoline nucleus by radical attack of a norcholane substituent. The newly synthesized hybrids were evaluated in vitro for their antitrypanosomal, antileishmanial and antiplasmodial activities, along with their cytotoxicity against WI38, a normal human fibroblast cell line. Seven compounds (4d, 4f, 4h, 5b, 5d, 5f, 5h) showed promising trypanocidal activity with IC₅₀ values in the same range as the commercial drug suramine. Moreover all the 16 hybrids showed antiplasmodial activity (IC₅₀ ≤ 6 μg/ml), particularly those containing a nor-chenodeoxycholane moiety (4b, 4d, 4f, 4h, 5b, 5d, 5f, 5h) with IC₅₀ values comparable to those of the natural alkaloids, and selectivity indices in the range of 5.6-15.7.
|
Inhibition of human recombinant microsomal CYP2D6 using {3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin} as substrate assessed as remaining activity at 10 uM after 30 mins by spectrofluorimetric analysis relative to control
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : New serotonin 5-HT1A receptor agonists endowed with antinociceptive activity in vivo.
Year : 2013
Volume : 56
Issue : 20
First Page : 7851
Last Page : 7861
Authors : Valhondo M, Marco I, Martín-Fontecha M, Vázquez-Villa H, Ramos JA, Berkels R, Lauterbach T, Benhamú B, López-Rodríguez ML.
Abstract : We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2-ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (Ki = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ∼ 3 h and CLint = 3.5 mL/min/kg, at 5 μM), and a low level of protein binding (25%, at 5 μM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.
|
Inhibition of CYP3A4 in human liver microsomes assessed as midazolam hydroxylation to 1'-hydroxymidazolam at 10 uM after 10 mins relative to control
|
Homo sapiens
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP2D6 in human liver microsomes assessed as bufuralol hydroxylation to 4'-hydroxybufuralol at 10 uM after 10 mins relative to control
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP1A2 in human liver microsomes assessed as phenacetin demethylation to acetaminophen at 10 uM after 10 mins relative to control
|
Homo sapiens
|
23.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP2C9 in human liver microsomes assessed as tolbutamide hydroxylation to hydroxytolbutamide at 10 uM after 10 mins relative to control
|
Homo sapiens
|
9.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP2D6 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
95.07
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Hepatitis C Virus NS5A Inhibitors Containing a Benzidine Core.
Year : 2014
Volume : 5
Issue : 3
First Page : 255
Last Page : 258
Authors : Bae IH, Choi JK, Chough C, Keum SJ, Kim H, Jang SK, Kim BM.
Abstract : Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.
|
Inhibition of recombinant CYP2D6 (unknown origin) using 7-methoxy-4-trifluoromethylcoumarin as substrate
|
Homo sapiens
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors.
Year : 2014
Volume : 57
Issue : 11
First Page : 4640
Last Page : 4660
Authors : Suchaud V, Bailly F, Lion C, Calmels C, Andréola ML, Christ F, Debyser Z, Cotelle P.
Abstract : We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.
|
Inhibition of human CYP2D6 at 10 uM
|
Homo sapiens
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Development of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-amidinophenylbenzamides as potent inhibitors of venezuelan equine encephalitis virus.
Year : 2014
Volume : 57
Issue : 20
First Page : 8608
Last Page : 8621
Authors : Schroeder CE, Yao T, Sotsky J, Smith RA, Roy S, Chu YK, Guo H, Tower NA, Noah JW, McKellip S, Sosa M, Rasmussen L, Smith LH, White EL, Aubé J, Jonsson CB, Chung D, Golden JE.
Abstract : Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 μM, CC50 > 50 μM) while limiting in vitro viral replication (EC90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg(-1) day(-1) and viral replication appeared to be inhibited through interference of viral nonstructural proteins.
|
Inhibition of CYP2D6 (unknown origin) using AMMC by fluorescence assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5α-androstane-3α,17β-diol derivatives.
Year : 2014
Volume : 22
Issue : 21
First Page : 5847
Last Page : 5859
Authors : Ayan D, Maltais R, Hospital A, Poirier D.
Abstract : Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5α-androstane-3α,17β-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2β and an ethinyl at position 17α, showed very good antiproliferative activity among the five cancer cell lines studied (IC50=0.1, 0.1, 0.1, 2.0 and 1.1 μM for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion.
|
Inhibition of recombinant human CYP2D6 preincubated at 10 uM for 5 mins before fluorescent substrate addition by fluorescence assay
|
Homo sapiens
|
21.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of CYP2D6 in human liver microsome
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists.
Year : 2014
Volume : 24
Issue : 17
First Page : 4271
Last Page : 4275
Authors : Park EJ, Ahn YG, Jung SH, Bang HJ, Kim M, Hong DJ, Kim J, Suh KH, Kim YJ, Kim D, Kim EY, Lee K, Min KH.
Abstract : Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.
|
Inhibition of human ERG expressed in CHL cells assessed as tail current at 10 uM after 7 mins by patch clamp assay relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Antimalarial activity of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives.
Year : 2015
Volume : 58
Issue : 8
First Page : 3411
Last Page : 3431
Authors : Korotchenko V, Sathunuru R, Gerena L, Caridha D, Li Q, Kreishman-Deitrick M, Smith PL, Lin AJ.
Abstract : Chloroquine (CQ) has been used as first line malaria therapeutic drug for decades. Emergence of CQ drug-resistant Plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. Mefloquine (MQ) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage P. falciparum (Pf). However, serious CNS toxicity of MQ has compromised its clinical value as a prophylaxis drug. Therefore, new and inexpensive antimalarial drugs with no cross-resistance to CQ or CNS toxicity are urgently needed to combat this deadly human disease. In this study, a series of new 4-amidinoquinoline (4-AMQ) and 10-amidinobenzonaphthyridine (10-AMB) derivatives were designed, prepared, and assessed to search for new therapeutic agents to replace CQ and MQ. The new derivatives displayed high activity in vitro and in vivo, with no cross-resistance to CQ, and none were toxic in mice up to 160 mpk × 3. The best compound shows IC50 < 1 ng/mL against D6, W2 and C235 Pf clones, low inhibitory activity in hERG K(+) channel blockage testing, negativity in the Ames test, and 5/5 cure @ <15 mpk × 3 in mice infected with Plasmodium berghei. In addition to these desirable pharmacological profiles, compound 13b, one of the most active compounds, is metabolically stable in both human and mouse liver microsomal preparations and has a plasma t(1/2) of 50 h in mice, which made it a good MQ replacement candidate.
|
Inhibition of hERG K channel
|
None
|
300.0
nM
|
|
Journal : Cardiovasc. Res.
Title : Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.
Year : 2011
Volume : 91
First Page : 53
Last Page : 61
Authors : Mirams GR, Cui Y, Sher A, Fink M, Cooper J, Heath BM, McMahon NC, Gavaghan DJ, Noble D.
Abstract : The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
|
Inhibition of OCTN1 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]ergothioneine substrate uptake at 1500 uM by liquid scintillation counting
|
Homo sapiens
|
83.9
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OCTN2 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]carnitine substrate uptake at 1500 uM by liquid scintillation counting
|
Homo sapiens
|
89.9
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Antiplasmodial activity against Plasmodium falciparum 3D7 assessed as reduction in parasite viability by parasite lactate dehydrogenase assay
|
Plasmodium falciparum 3D7
|
194.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities.
Year : 2015
Volume : 100
First Page : 10
Last Page : 17
Authors : Leverrier A, Bero J, Cabrera J, Frédérich M, Quetin-Leclercq J, Palermo JA.
Abstract : In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 μM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 μM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure-activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s.
|
Inhibition of CYP2D6 (unknown origin) at 1 uM by luminescent readout-based method
|
Homo sapiens
|
96.25
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40).
Year : 2015
Volume : 25
Issue : 16
First Page : 3105
Last Page : 3111
Authors : Zahanich I, Kondratov I, Naumchyk V, Kheylik Y, Platonov M, Zozulya S, Krasavin M.
Abstract : A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved.
|
Inhibition of CYP2D6 (unknown origin)
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model.
Year : 2015
Volume : 101
First Page : 627
Last Page : 639
Authors : Roman BI, De Ryck T, Patronov A, Slavov SH, Vanhoecke BW, Katritzky AR, Bracke ME, Stevens CV.
Abstract : Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.
|
Inhibition of CYP2D6 (unknown origin) using luciferin tagged substrate preincubated for 10 mins before substrate addition
|
Homo sapiens
|
30.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
Year : 2015
Volume : 103
First Page : 210
Last Page : 222
Authors : Elkamhawy A, Viswanath AN, Pae AN, Kim HY, Heo JC, Park WK, Lee CO, Yang H, Kim KH, Nam DH, Seol HJ, Cho H, Roh EJ.
Abstract : Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.
|
Inhibition of CYP2D6 (unknown origin) at 1 uM by P450-glo assay
|
Homo sapiens
|
96.25
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold.
Year : 2016
Volume : 24
Issue : 13
First Page : 2954
Last Page : 2963
Authors : Krasavin M, Lukin A, Zhurilo N, Kovalenko A, Zahanich I, Zozulya S, Moore D, Tikhonova IG.
Abstract : Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.
|
Inhibition of human recombinant CYP2D6 using MFC as substrate incubated for 40 mins by fluorimetry
|
Homo sapiens
|
17.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4.
Year : 2016
Volume : 117
First Page : 256
Last Page : 268
Authors : Billamboz M, Suchaud V, Bailly F, Lion C, Andréola ML, Christ F, Debyser Z, Cotelle P.
Abstract : Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate after 10 mins by LC-MS analysis
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism.
Year : 2016
Volume : 59
Issue : 7
First Page : 3340
Last Page : 3352
Authors : Carosati E, Cosimelli B, Ioan P, Severi E, Katneni K, Chiu FC, Saponara S, Fusi F, Frosini M, Matucci R, Micucci M, Chiarini A, Spinelli D, Budriesi R.
Abstract : We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC50 = 0.022 μM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies.
|
Inhibition of CYP2D6 in human liver microsomes using bufuralol as substrate at 10 uM preincubated for 5 mins followed by NADPH addition measured after 10 mins by LC-MS/MS analysis relative to control
|
Homo sapiens
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.
Year : 2016
Volume : 59
Issue : 10
First Page : 4913
Last Page : 4925
Authors : Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB.
Abstract : Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
|
Inhibition of recombinant human CYP2D6 by P450-Glo luminescence assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists.
Year : 2016
Volume : 59
Issue : 10
First Page : 4601
Last Page : 4610
Authors : Smutny T, Nova A, Drechslerová M, Carazo A, Hyrsova L, Hrušková ZR, Kuneš J, Pour M, Špulák M, Pavek P.
Abstract : Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with pregnane X (PXR) and aryl hydrocarbon (AHR) receptors, it is referred to as "xenobiotic receptor". The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxyphenyl)quinazoline derivatives. The compounds are even more potent activators of human CAR than is prototype 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The three most potent ligands are at the same time extremely potent activators of the other xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor, which regulate major xenobiotic-metabolizing enzymes and efflux transporters. Thus, the novel CAR ligands can be also considered as constituting the first class of potent pan-xenobiotic receptor ligands that can serve as potential antidotes boosting overall metabolic elimination of xenobiotic or toxic compounds.
|
Inhibition of CYP2D6 in pooled human hepatic microsomes using dextromethorphan substrate in presence of NADPH
|
Homo sapiens
|
41.3
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na+/H+ Exchanger Type 3 (NHE3).
Year : 2016
Volume : 59
Issue : 19
First Page : 8812
Last Page : 8829
Authors : Rackelmann N, Matter H, Englert H, Follmann M, Maier T, Weston J, Arndt P, Heyse W, Mertsch K, Wirth K, Bialy L.
Abstract : The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na+/H+ exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC/MS/MS method
|
Homo sapiens
|
151.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies.
Year : 2017
Volume : 25
Issue : 2
First Page : 750
Last Page : 758
Authors : Zhao D, Zhao S, Zhao L, Zhang X, Wei P, Liu C, Hao C, Sun B, Su X, Cheng M.
Abstract : Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization.
|
Inhibition of CYP2D6 in human liver microsomes using bufuralol as substrate after 5 to 15 mins
|
Homo sapiens
|
35.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.
Year : 2017
Volume : 8
Issue : 3
First Page : 321
Last Page : 326
Authors : Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y, Almo SC, Jacobson MP, Hua L, Xu Q, Gwaltney SL, Yee C, Harris J, Morgan BP, James J, Xu D, Hutchaleelaha A, Paulvannan K, Oksenberg D, Li Z.
Abstract : We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC/MS/MS analysis
|
Homo sapiens
|
135.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents.
Year : 2017
Volume : 137
First Page : 96
Last Page : 107
Authors : Zhao S, Zhang X, Wei P, Su X, Zhao L, Wu M, Hao C, Liu C, Zhao D, Cheng M.
Abstract : To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
|
Inhibition of CYP2D6 in human liver microsomes assessed as dextromethorphan O-demethylation after 4 to 40 mins in presence of NADPH by LCMS analysis
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria.
Year : 2018
Volume : 26
Issue : 11
First Page : 2996
Last Page : 3005
Authors : O' Neill PM, Stocks PA, Sabbani S, Roberts NL, Amewu RK, Shore ER, Aljayyoussi G, Angulo-Barturén I, Belén M, Jiménez-Díaz, Bazaga SF, Martínez MS, Campo B, Sharma R, Charman SA, Ryan E, Chen G, Shackleford DM, Davies J, Nixon GL, Biagini GA, Ward SA.
Abstract : A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
118.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51.
Year : 2018
Volume : 26
Issue : 12
First Page : 3242
Last Page : 3253
Authors : Zhao S, Wei P, Wu M, Zhang X, Zhao L, Jiang X, Hao C, Su X, Zhao D, Cheng M.
Abstract : To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
|
Inhibition of CYP2D6 in human liver microsomes at 2 uM using dextromethorphan as substrate by LC-MS/MS analysis relative to control
|
Homo sapiens
|
93.28
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings.
Year : 2018
Volume : 28
Issue : 18
First Page : 3050
Last Page : 3056
Authors : Sun Z, Zhou T, Pan X, Yang Y, Huan Y, Xiao Z, Shen Z, Liu Z.
Abstract : A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.
|
Inhibition of recombinant human CYP2D6 expressed in insect cell microsomes at 1 uM using Luciferin-ME EGE as substrate preincubated for 30 mins followed by NADPH addition measured after 45 mins by luminometric method
|
Homo sapiens
|
91.0
%
|
|
Journal : Eur J Med Chem
Title : Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo.
Year : 2018
Volume : 157
First Page : 368
Last Page : 379
Authors : Vesci L, Milazzo FM, Stasi MA, Pace S, Manera F, Tallarico C, Cini E, Petricci E, Manetti F, De Santis R, Giannini G.
Abstract : Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies.
|
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
|
10.07
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-1.55
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
12.62
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
8.31
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
15.14
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-0.46
%
|
|
|
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
|
2.25
%
|
|
|
Inhibition of human TASK3 expressed in Xenopus oocytes at 100 uM by whole cell patch clamp assay relative to control
|
Homo sapiens
|
42.2
%
|
|
Journal : J Med Chem
Title : TASK Channels Pharmacology: New Challenges in Drug Design.
Year : 2019
Volume : 62
Issue : 22
First Page : 10044
Last Page : 10058
Authors : Bedoya M, Rinné S, Kiper AK, Decher N, González W, Ramírez D.
Abstract : Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.
|
Inhibition of rat TASK3 expressed in African green monkey COS7 cells at 100 uM by outside-out patches based electrophysiology assay relative to control
|
Rattus norvegicus
|
37.0
%
|
|
Journal : J Med Chem
Title : TASK Channels Pharmacology: New Challenges in Drug Design.
Year : 2019
Volume : 62
Issue : 22
First Page : 10044
Last Page : 10058
Authors : Bedoya M, Rinné S, Kiper AK, Decher N, González W, Ramírez D.
Abstract : Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.
|
Inhibition of CYP2D6 in pooled human liver microsomes pre-incubated for 5 mins before NADPH addition and measured after 10 mins by UPLC-MS/MS analysis relative to control
|
Homo sapiens
|
78.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.
Year : 2019
Volume : 62
Issue : 23
First Page : 10563
Last Page : 10582
Authors : Ramdas V, Talwar R, Banerjee M, Joshi AA, Das AK, Walke DS, Borhade P, Dhayagude U, Loriya R, Gote G, Bommakanti A, Sivaram A, Agarwal G, Goswami A, Nigade P, Mehta M, Patil V, Modi D, Kumar H, Mallurwar S, Dash A, Modi F, Kuldharan S, Srivastava P, Singh M, Narasimham L, Gundu J, Sharma S, Kamboj RK, Palle VP.
Abstract : The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan substrate incubated for 10 mins in presence of NADPH
|
Homo sapiens
|
156.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of CYP2D6 (unknown origin) using beetle D-luciferin as substrate by CYP450-Glo assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : MedChemComm
Title : Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists.
Year : 2018
Volume : 9
Issue : 11
First Page : 1882
Last Page : 1890
Authors : Latacz G, Hogendorf AS, Hogendorf A, Lubelska A, Wierońska JM, Woźniak M, Cieślik P, Kieć-Kononowicz K, Handzlik J, Bojarski AJ.
Abstract : Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7, 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1AR.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate after 10 mins in presence of NADPH
|
Homo sapiens
|
156.0
nM
|
|
Journal : J Med Chem
Title : Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties.
Year : 2019
Volume : 62
Issue : 3
First Page : 1484
Last Page : 1501
Authors : Kang D, Zhang H, Wang Z, Zhao T, Ginex T, Luque FJ, Yang Y, Wu G, Feng D, Wei F, Zhang J, De Clercq E, Pannecouque C, Chen CH, Lee KH, Murugan NA, Steitz TA, Zhan P, Liu X.
Abstract : To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC<sub>50</sub> = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.
|
Inhibition of human CYP2D6 in human liver microsomes at 50 times IC50 concentration relative to control
|
Homo sapiens
|
97.9
%
|
|
Journal : J Med Chem
Title : Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors.
Year : 2019
Volume : 62
Issue : 3
First Page : 1138
Last Page : 1166
Authors : Vögerl K, Ong N, Senger J, Herp D, Schmidtkunz K, Marek M, Müller M, Bartel K, Shaik TB, Porter NJ, Robaa D, Christianson DW, Romier C, Sippl W, Jung M, Bracher F.
Abstract : The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate after 20 mins in presence of NADP by LC-MS/MS analysis
|
Homo sapiens
|
263.0
nM
|
|
Journal : J Med Chem
Title : Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.
Year : 2019
Volume : 62
Issue : 4
First Page : 2083
Last Page : 2098
Authors : Huang B, Chen W, Zhao T, Li Z, Jiang X, Ginex T, Vílchez D, Luque FJ, Kang D, Gao P, Zhang J, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X.
Abstract : Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.
|
Inhibition of human ERG expressed in HEK cell at 1 uM at -70 mV holding potential by patch clamp method relative to control
|
Homo sapiens
|
50.2
%
|
|
Journal : Bioorg Med Chem Lett
Title : Click chemistry for improvement in selectivity of quinazoline-based kinase inhibitors for mutant epidermal growth factor receptors.
Year : 2019
Volume : 29
Issue : 3
First Page : 477
Last Page : 480
Authors : Song J, Jang S, Lee JW, Jung D, Lee S, Min KH.
Abstract : Discovery of mutant-selective kinase inhibitors is one of the challenges in medicinal chemistry and is a main issue for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. We tried to improve the selectivity of pan-HER inhibitors for mutant EGFRs. Utilizing click chemistry, triazole-tethered quinazoline derivatives were synthesized, based on a quinazoline scaffold showing pan-HER inhibition. The representative compound 5j exhibited 17- and 52-fold improved selectivity for EGFR L858R/T790M over wild-type EGFR and HER2, respectively, and demonstrated 6.7-fold more potent antiproliferative activity against PC9 cells harboring EGFR-activating mutation than gefitinib. Although the described quinazolines did not surpass pyrimidines as 3rd generation EGFR inhibitors in terms of selectivity for mutant EGFRs, our approach might provide information that would help in the identification of mutant-selective compounds among pan-HER inhibitors using the quinazoline scaffold.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan substrate in presence of NADPH incubated for 10 mins
|
Homo sapiens
|
134.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel.
Year : 2020
Volume : 63
Issue : 3
First Page : 1298
Last Page : 1312
Authors : Kang D, Ruiz FX, Feng D, Pilch A, Zhao T, Wei F, Wang Z, Sun Y, Fang Z, De Clercq E, Pannecouque C, Arnold E, Liu X, Zhan P.
Abstract : Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.
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Inhibition of human CYP2D6 in presence of NADPH by luciferase reporter gene assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of New 1-(Aryl-1 H-pyrrolyl)(phenyl)methyl-1 H-imidazole Derivatives as Antiprotozoal Agents.
Year : 2019
Volume : 62
Issue : 3
First Page : 1330
Last Page : 1347
Authors : Saccoliti F, Madia VN, Tudino V, De Leo A, Pescatori L, Messore A, De Vita D, Scipione L, Brun R, Kaiser M, Mäser P, Calvet CM, Jennings GK, Podust LM, Pepe G, Cirilli R, Faggi C, Di Marco A, Battista MR, Summa V, Costi R, Di Santo R.
Abstract : We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC<sub>50</sub> within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure-activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a-c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.
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Inhibition of human CYP2D6 by fluorescence method
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogues as Potential Clinical Antiarrhythmic Agents.
Year : 2019
Volume : 62
Issue : 22
First Page : 10124
Last Page : 10143
Authors : Adebesin AM, Wesser T, Vijaykumar J, Konkel A, Paudyal MP, Lossie J, Zhu C, Westphal C, Puli N, Fischer R, Schunck WH, Falck JR.
Abstract : 17(R),18(S)-Epoxyeicosatetraenoic acid (EEQ) is a cytochrome P450 metabolite of eicosapentaenoic acid (EPA) and a powerful negative chronotrope with low nanomolar activity in a neonatal rat cardiomyocyte (NRCM) arrhythmia model. Prior studies identified oxamide 2b as a soluble epoxide hydrolase (sEH) stable replacement but unsuitable for in vivo applications due to limited oral bioavailability and metabolic stability. These ADME limitations have been addressed in an improved generation of negative chronotropes, e.g., 4 and 16, which were evaluated as potential clinical candidates.
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Inhibition of human recombinant CYP2D6 using luciferin as substrate preincubated for 10 mins followed by substrate addition and measured after 50 mins in presence of NADPH by CYP450-Glo assay
|
Homo sapiens
|
6.9
nM
|
|
Journal : Bioorg Med Chem
Title : Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H<sub>3</sub> receptor ligands.
Year : 2017
Volume : 25
Issue : 20
First Page : 5341
Last Page : 5354
Authors : Łażewska D, Kaleta M, Schwed JS, Karcz T, Mogilski S, Latacz G, Olejarz A, Siwek A, Kubacka M, Lubelska A, Honkisz E, Handzlik J, Filipek B, Stark H, Kieć-Kononowicz K.
Abstract : Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H<sub>3</sub> receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a K<sub>i</sub> value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; K<sub>i</sub>=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; K<sub>i</sub>=34nM), classified as antagonists in a cAMP accumulation assay (IC<sub>50</sub>=4 and 9nM, respectively), were studied in detail. Compounds 14 and 16 blocked RAMH-induced dipsogenia in rats (ED<sub>50</sub> of 2.72mg/kg and 1.75mg/kg respectively), and showed high selectivity (hH<sub>4</sub>R vs hH<sub>3</sub>R>600-fold) and low toxicity (hERG inhibition: IC<sub>50</sub>>1.70µM; hepatotoxicity IC<sub>50</sub>>12.5µM; non-mutagenic up to 10µM). Furthermore, the metabolic stability was evaluated in vitro on human liver microsomes (HLMs) and/or rat liver microsomes (RLMs). Metabolites produced were analyzed and tentatively identified by UPLC-MS techniques. The results demonstrated easy hydroxylation of the biphenyl ring.
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Inhibition of CYP2D6 (unknown origin) expressed in insect cell microsomes using dibenzylfluorescein substrate by fluorescence based assay
|
Homo sapiens
|
7.3
nM
|
|
Journal : J Med Chem
Title : Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A<sub>2B</sub> Adenosine Receptor Antagonists.
Year : 2020
Volume : 63
Issue : 14
First Page : 7721
Last Page : 7739
Authors : Mallo-Abreu A, Prieto-Díaz R, Jespers W, Azuaje J, Majellaro M, Velando C, García-Mera X, Caamaño O, Brea J, Loza MI, Gutiérrez-de-Terán H, Sotelo E.
Abstract : A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A<sub>2B</sub>AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-<i>a</i>]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (<i>K<sub>i</sub></i> < 30 nM) and exquisite selectivity. The structure-activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between <i>h</i>A<sub>2B</sub>AR and the eutomer of the most attractive novel antagonist (<i><b>S</b></i>)-<b>18g</b> (<i>K<sub>i</sub></i> = 3.66 nM) was validated.
|
Inhibition of CYP2D6 in human liver microsome using probe substrate measured after 20 mins in presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
134.0
nM
|
|
Journal : J Med Chem
Title : Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10829
Last Page : 10854
Authors : Zhao T,Meng Q,Sun Z,Chen Y,Ai W,Zhao Z,Kang D,Dong Y,Liang R,Wu T,Pang J,Liu X,Zhan P
Abstract : Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
|
Inhibition of CYP2D6 in human liver microsomes at 10 uM using dextromethorphan as substrate preincubated for 5 mins followed by NADPH addition and measured after 20 mins by LC-MS/MS analysis relative to control
|
Homo sapiens
|
89.0
%
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Inhibition of human recombinant CYP2D6
|
Homo sapiens
|
8.1
nM
|
|
Journal : J Med Chem
Title : Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT Receptor-Biased Agonists with Robust Antidepressant-like Activity.
Year : 2019
Volume : 62
Issue : 5.0
First Page : 2750
Last Page : 2771
Authors : Sniecikowska J,Gluch-Lutwin M,Bucki A,Więckowska A,Siwek A,Jastrzebska-Wiesek M,Partyka A,Wilczyńska D,Pytka K,Pociecha K,Cios A,Wyska E,Wesołowska A,Pawłowski M,Varney MA,Newman-Tancredi A,Kolaczkowski M
Abstract : Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT receptors. The compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5-HT receptor affinity, >1000-fold selectivity versus noradrenergic α, dopamine D, serotonin 5-HT, histamine H, and muscarinic M receptors, and favorable druglike properties (CNS-MPO, Fsp, LELP). The lead structure, (3-chloro-4-fluorophenyl)(4-fluoro-4-(((2-(pyridin-2-yloxy)ethyl)amino)methyl)piperidin-1-yl)methanone (17, NLX-204), displayed high selectivity in the SafetyScreen44 panel (including hERG channel), high solubility, metabolic stability, and Caco-2 penetration and did not block CYP3A4, CYP2D6 isoenzymes, or P-glycoprotein. Preliminary in vivo studies confirmed its promising pharmacokinetic profile. 17 also robustly stimulated ERK1/2 phosphorylation in rat cortex and showed highly potent (MED = 0.16 mg/kg) and efficacious antidepressant-like activity, totally eliminating immobility in the rat Porsolt test. These data suggest that the present 5-HT receptor-biased agonists could constitute promising antidepressant drug candidates.
|
Inhibition of CYP2D6 in human liver microsomes after 20 mins by LC-MS/MS analysis
|
Homo sapiens
|
44.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis.
Year : 2020
Volume : 63
Issue : 17
First Page : 9316
Last Page : 9339
Authors : Zhao H,Wang B,Fu L,Li G,Lu H,Liu Y,Sheng L,Li Y,Zhang B,Lu Y,Ma C,Huang H,Zhang D,Lu Y
Abstract : Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound 19c demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, 19c appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate incubated for 5 mins followed by NADPH addition and measured after 20 mins by LC-MS/MS analysis
|
Homo sapiens
|
35.6
nM
|
|
Journal : Eur J Med Chem
Title : Substituted benzothiophene and benzofuran derivatives as a novel class of bone morphogenetic Protein-2 upregulators: Synthesis, anti-osteoporosis efficacies in ovariectomized rats and a zebrafish model, and ADME properties.
Year : 2020
Volume : 200
First Page : 112465
Last Page : 112465
Authors : Xue ST,Zhang L,Xie ZS,Jin J,Guo HF,Yi H,Liu ZY,Li ZR
Abstract : The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.
|
Inhibition of CYP2D6 in human liver microsomes using Dextromethorphan as substrate measured after 20 mins by LC-MS/MS analysis
|
Homo sapiens
|
40.8
nM
|
|
|
Inhibition of CYP2D6 in human liver Microsome using dextromethorphan as substrate preincubated for 10 mins followed by NADPH addition and further incubated for 10 mins as substrate by LC-MS/MS analysis relative to control
|
Homo sapiens
|
96.2
%
|
|
|
Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate in presence of NADPH incubated for 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
120.0
nM
|
|
|
Inhibition of CYP2D6 in human liver microsomes using bufuralol as substrate incubated for 10 mins in presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
60.0
nM
|
|
|
Inhibition of CYP2D6 in human liver microsome using dextromethorphan as substrate
|
Homo sapiens
|
64.0
nM
|
|
|
Inhibition of CYP2D6 (unknown origin) at 1 uM using dextromethorphan as substrate relative to control
|
Homo sapiens
|
91.3
%
|
|
|
Inhibition of CYP2D6 (unknown origin) using quinidine as substrate
|
Homo sapiens
|
18.0
nM
|
|
