|
Binding affinity towards human 5-hydroxytryptamine 6 receptor
|
None
|
71.0
nM
|
|
Journal : J. Med. Chem.
Title : Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
Year : 2003
Volume : 46
Issue : 14
First Page : 2795
Last Page : 2812
Authors : Glennon RA.
|
Binding affinity towards rat 5-hydroxytryptamine 7 receptor
|
None
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7).
Year : 2003
Volume : 46
Issue : 14
First Page : 2795
Last Page : 2812
Authors : Glennon RA.
|
Binding affinity of compound towards Dopamine receptor D2 using [3H]raclopride (1.2 nM) ligand in striatum bovine was determined
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : New benzocycloalkylpiperazines, potent and selective 5-HT1A receptor ligands.
Year : 1997
Volume : 40
Issue : 6
First Page : 952
Last Page : 960
Authors : el Ahmad Y, Laurent E, Maillet P, Talab A, Teste JF, Dokhan R, Tran G, Ollivier R.
Abstract : A series of 1-(benzocycloalkyl)-4-(benzamidolkyl)piperazine derivatives was prepared in order to obtain compounds with a high affinity and selectivity for 5-HT1A receptors. The modifications of aromatic substituents, the length of the alkyl chain, and the size of the ring were explored. Most of N-(1,2,3,4-tetrahydronaphthyl)-N'-(benzamidoethyl)piperazines (32-37) were bound to 5-HT1A receptors in a nanomolar range and presented a high degree of selectivity. After resolution, levorotatory enantiomers showed affinity and selectivity higher than those of dextrorotory ones for 5-HT1A sites. The agonist type activity of selected derivatives was also confirmed in vitro on the inhibition of the activation of adenylate cyclase induced by forskolin and, in vivo, on the induction of the lower lip retraction in rats.
|
Inhibition of [3H]haloperidol binding to dopamine receptors in rat striatal membranes.
|
None
|
0.4
nM
|
|
Inhibition of [3H]haloperidol binding to dopamine receptors in rat striatal membranes.
|
None
|
0.48
nM
|
|
Journal : J. Med. Chem.
Title : 1-[3-(Diarylamino)propyl]piperidines and related compounds, potential antipsychotic agents with low cataleptogenic profiles.
Year : 1985
Volume : 28
Issue : 5
First Page : 606
Last Page : 612
Authors : Wise LD, Pattison IC, Butler DE, DeWald HA, Lewis EP, Lobbestael SJ, Nordin IC, Poschel BP, Coughenour LL.
Abstract : On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).
|
Inhibition of [3H]haloperidol binding to dopamine receptors in rat striatal membranes at 10e-8 M.
|
None
|
94.0
%
|
|
Inhibition of [3H]haloperidol binding to dopamine receptors in rat striatal membranes at 10e-8 M.
|
None
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : 1-[3-(Diarylamino)propyl]piperidines and related compounds, potential antipsychotic agents with low cataleptogenic profiles.
Year : 1985
Volume : 28
Issue : 5
First Page : 606
Last Page : 612
Authors : Wise LD, Pattison IC, Butler DE, DeWald HA, Lewis EP, Lobbestael SJ, Nordin IC, Poschel BP, Coughenour LL.
Abstract : On the basis of a structural model of the postsynaptic dopaminergic antagonist pharmacophore, a series of 1-[3-(diarylamino)propyl]piperidines and related compounds was synthesized and evaluated for potential antipsychotic activity. For a rapid measure of activity, the target compounds were initially screened in vitro for inhibition of [3H]haloperidol binding and in vivo in a test of locomotor activity. Behavioral efficacy of compounds identified from the initial screens was more accurately measured in rats by using a suppression of high base-line medial forebrain bundle self-stimulation test model. The propensity of these compounds for causing extrapyramidal side effects was evaluated by using a rat catalepsy method. On the basis of these test models, we have shown that the methine carbon of the 1-(4,4-diarylbutyl)piperidines can be advantageously replaced with a nitrogen atom. The 1-[3-(diarylamino)propyl]piperidines were less cataleptic than the corresponding 1-(4,4-diarylbutyl)piperidines. The compounds with the widest separation between efficacious dose and cataleptic dose are 8-[3-[bis(4-fluorophenyl)amino]propyl]-1-phenyl-1,3,8-triazaspiro [4. 5]decan-4-one (6), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-4-piperidinyl]-1,3-dihydro- 2H-benzimidazol-2-one (11), 1-[1-[3-[bis(4-fluorophenyl)amino]propyl]-1,2,3,6-tetrahydro-4- pyridinyl]-1,3-dihydro-2H-benzimidazol-2-one (22), and 1-[3-[bis(4-fluorophenyl)amino]propyl]-4-(2-methoxyphenyl)piperazine (26).
|
Binding affinity towards Dopamine receptor D2
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
Year : 2003
Volume : 46
Issue : 11
First Page : 2017
Last Page : 2022
Authors : Pearlstein R, Vaz R, Rampe D.
|
K+ channel blocking activity in human embryonic kidney cells expressing HERG Kv11.1
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
Year : 2002
Volume : 45
Issue : 18
First Page : 3844
Last Page : 3853
Authors : Cavalli A, Poluzzi E, De Ponti F, Recanatini M.
Abstract : In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.
|
Compound was evaluated for the inhibition of Locomotion-Screen falloff test, at dose (mg/Kg) = 10; 60-100%
|
Mus musculus
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : (1,3-Dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones. A series of novel central nervous system depressants.
Year : 1984
Volume : 27
Issue : 11
First Page : 1396
Last Page : 1400
Authors : Butler DE, Wise LD, DeWald HA.
Abstract : A series of novel (1,3-dialkyl-5-amino-1H-pyrazol-4-yl)arylmethanones was synthesized. Pharmacological evaluation of these compounds demonstrated central nervous system depressant activity, potential anticonvulsant properties, and a low order of acute toxicity. In addition, selected compounds showed potential antipsychotic effects. This report focuses on the synthesis and structure-activity relationships of these compounds. (5-Amino-1-ethyl-3-methyl-1H-pyrazol-4-yl)(2-chlorophenyl) methanone (21) was the most active compound against pentylenetetrazole-induced convulsions. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-chlorophenyl)methanone (4) also has a favorable anticonvulsant depression ratio. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-trifluoromethylphenyl)methan one (8), (5-amino-1,3-dimethyl-1H-pyrazol-4-yl)(3-thienyl)methanone (13), and (5-amino-3-ethyl-1-methyl-1H-pyrazol-4-yl)phenylmethanone (14) are very potent depressants. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl)(2-thienyl)methanone (12) possessed marked central depressant activity without anticonvulsant activity and without impairment of motor functioning. (5-Amino-1,3-dimethyl-1H-pyrazol-4-yl) (2-fluorophenyl)methanone (2) has a behavioral profile suggestive of antipsychotic activity and gave a positive Ames test result.
|
Binding affinity against opioid receptor kappa 1 by using [3H]U-69593 as radioligand
|
None
|
990.0
nM
|
|
Journal : J. Med. Chem.
Title : From hit to lead. Analyzing structure-profile relationships.
Year : 2001
Volume : 44
Issue : 21
First Page : 3391
Last Page : 3401
Authors : Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Déprez B.
Abstract : Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.
|
Inhibition of P-glycoprotein using calcein-AM assay transfected in porcine PBCEC
|
None
|
800.0
nM
|
|
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.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
37.0
%
|
|
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.
|
Binding affinity against mu opioid receptor using [3H]DAMGO
|
Homo sapiens
|
372.0
nM
|
|
Journal : J. Med. Chem.
Title : From hit to lead. Analyzing structure-profile relationships.
Year : 2001
Volume : 44
Issue : 21
First Page : 3391
Last Page : 3401
Authors : Poulain R, Horvath D, Bonnet B, Eckhoff C, Chapelain B, Bodinier MC, Déprez B.
Abstract : Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.
|
Inhibition of human Potassium channel HERG expressed in mammalian cells
|
Homo sapiens
|
50.12
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 K+ channel activity in CHO cells expressing HERG Kv11.1
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
Year : 2003
Volume : 13
Issue : 10
First Page : 1829
Last Page : 1835
Authors : Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, Korolev AM, Lysenkova LN, Miroshnikova OV, Hendrix J, Rampe D.
Abstract : A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA. A homology model of HERG was constructed from the crystal structure of the open MthK potassium channel. A complementary relationship between our CoMSiA and homology models is apparent when the long inhibitor axis is oriented parallel to the longitudinal axis of the pore, with the tail region pointed toward the selectivity filter. The key elements of the pharmacophore, the CoMSiA and the homology model are: (1) The hydrophobic feature optimally consists of an aromatic group that is capable of engaging in pi-stacking with a Phe656 side chain. Optionally, a second aromatic or hydrophobic group present in some inhibitors may contact an additional Phe656 side chain. (2) The basic nitrogen appears to undergo a pi-cation interaction with Tyr652. (3) The pore diameter (12A+), and depth of the selectivity loop relative to the intracellular opening, act as constraints on the conformation-dependent inhibitor dimensions.
|
Inhibitory activity against Potassium channel HERG
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior.
Year : 2003
Volume : 46
Issue : 11
First Page : 2017
Last Page : 2022
Authors : Pearlstein R, Vaz R, Rampe D.
|
Inhibitory activity against type IIA sodium channel in CNaIIA-1 cell line expressed in CHO cells
|
None
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : A structure-activity relationship study of novel phenylacetamides which are sodium channel blockers.
Year : 1996
Volume : 39
Issue : 7
First Page : 1514
Last Page : 1520
Authors : Roufos I, Hays S, Schwarz RD.
Abstract : A structure-activity relationship study of a series of novel Na(+) channel blockers, structurally related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenylbenzeneacetamide (1, PD85639) is described. The diphenylacetic acid portion of the molecule was left unchanged throughout the study, while structural features in the amine portion and the amide alkyl linkage of the molecule were modified. The compounds were tested for inhibition of veratridine-stimulated Na(+) influx in CHO cells expressing type IIA Na(+) channels. Several derivatives show a trend toward more potent Na+ channel blockade activity with increasing lipophilicity of the amine portion of the molecule. The presence of a phenyl ring near the amine increases inhibitory potency. A three-carbon spacer between the amide and amine is optimal, and a secondary amide linkage is preferred.
|
Inhibitory concentration against potassium channel HERG
|
None
|
50.12
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 voltage-gated potassium channel subunit Kv11.1 (ERG K+ channel) in open state
|
Homo sapiens
|
18.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A two-state homology model of the hERG K+ channel: application to ligand binding.
Year : 2005
Volume : 15
Issue : 6
First Page : 1737
Last Page : 1741
Authors : Rajamani R, Tounge BA, Li J, Reynolds CH.
Abstract : Homology models based on available K+ channel structures have been used to construct a multiple state representation of the hERG cardiac K+ channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56 kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability.
|
Displacement of [3H]Astemizole from hERG expressed in HEK293 cells at 10 uM
|
Homo sapiens
|
42.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Ureas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides.
Year : 2006
Volume : 16
Issue : 20
First Page : 5303
Last Page : 5308
Authors : Lau JF, Jeppesen CB, Rimvall K, Hohlweg R.
Abstract : A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition.
|
Inhibition of human ERG channel in HEK293 cells by voltage-clamp method
|
Homo sapiens
|
3.02
nM
|
|
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.
|
Inhibition of human ERG channel
|
Homo sapiens
|
54.6
nM
|
|
Inhibition of human ERG channel
|
Homo sapiens
|
54.6
nM
|
|
Journal : J. Med. Chem.
Title : Side chain flexibilities in the human ether-a-go-go related gene potassium channel (hERG) together with matched-pair binding studies suggest a new binding mode for channel blockers.
Year : 2009
Volume : 52
Issue : 14
First Page : 4266
Last Page : 4276
Authors : Zachariae U, Giordanetto F, Leach AG.
Abstract : The cardiac hERG K(+) channel constitutes a long-standing and expensive antitarget for the drug industry. From a study of the flexibility of hERG around its internal binding cavity, we have developed a new structural model of drug binding to hERG, which involves binding orthogonal to the pore channel and therefore can exploit the up to 4-fold symmetry of the tetrameric channel. This binding site has a base formed by four tyrosine side chains that complement reported ligand-based pharmacophores. The model is able to rationalize reduced hERG potency in matched molecular pair studies and suggests design guidelines to optimize against hERG not relying simply on lipophilicity reduction. The binding model also suggests a molecular mechanism for the link between high-affinity hERG binding and C-type inactivation.
|
Inhibition of human ERG expressed in CHO cells by whole cell patch clamp technique
|
Homo sapiens
|
50.12
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 ERG in MCF7 cells
|
Homo sapiens
|
18.2
nM
|
|
Journal : Eur. J. Med. Chem.
Title : GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers.
Year : 2009
Volume : 44
Issue : 5
First Page : 1926
Last Page : 1932
Authors : Ermondi G, Visentin S, Caron G.
Abstract : The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844-53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K(+) channel blocking activity. As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.
|
Inhibition of dopamine D2 receptor
|
None
|
29.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and T-type calcium channel blocking activity of novel diphenylpiperazine compounds, and evaluation of in vivo analgesic activity.
Year : 2010
Volume : 18
Issue : 16
First Page : 5938
Last Page : 5944
Authors : Kam YL, Rhee HK, Rhim H, Back SK, Na HS, Choo HY.
Abstract : Novel diphenylpiperazine derivatives were synthesized and evaluated for their inhibitory activity against T-type calcium channel by whole-cell patch clamp recordings on HEK293 cells. Among the test compounds, 2 and 3d were effective in decreasing the response to formalin in both the first and second phases and demonstrated antiallodynic effects in a rat model of neuropathic pain.
|
Inhibition of internalization of Listeria monocytogenes 10403S into murine J774 cells pretreated at 18.1 uM for 2 hrs
|
Listeria monocytogenes 10403S
|
75.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of internalization of Listeria monocytogenes 10403S into murine Raw 264.7 cells pretreated at 18.1 uM for 2 hrs
|
Listeria monocytogenes 10403S
|
95.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of internalization of Bacillus subtilis into murine murine bone marrow macrophages pretreated at 18.1 uM for 2 hrs
|
Bacillus subtilis
|
73.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of internalization of Salmonella enterica serovar Typhimurium into murine murine bone marrow macrophages pretreated at 18.1 uM for 2 hrs
|
Salmonella enterica subsp. enterica serovar Typhimurium
|
64.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of internalization of Escherichia coli K-12 into murine murine bone marrow macrophages pretreated at 18.1 uM for 2 hrs
|
Escherichia coli K-12
|
60.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of internalization of Listeria monocytogenes DH-L1252 into murine bone marrow macrophages assessed as reduction in vacuolar escape of bacteria using phalloidin staining
|
Listeria monocytogenes
|
26.3
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Antimicrobial activity against Listeria monocytogenes 10403S infected in L2 cells assessed as decrease in plaque size at 18.1 uM after 1 hr
|
Listeria monocytogenes 10403S
|
47.1
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of Listeria monocytogenes 10403S entry into murine bone marrow macrophages at 18.1 uM after 30 mins in calcium-free medium
|
Listeria monocytogenes 10403S
|
95.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
Year : 2009
Volume : 53
Issue : 2
First Page : 756
Last Page : 764
Authors : Lieberman LA, Higgins DE.
Abstract : We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
|
Inhibition of T-type alpha1G calcium channel
|
None
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Facile synthesis and biological evaluation of 3,3-diphenylpropanoyl piperazines as T-type calcium channel blockers.
Year : 2011
Volume : 21
Issue : 1
First Page : 215
Last Page : 219
Authors : Choi YH, Baek du J, Seo SH, Lee JK, Pae AN, Cho YS, Min SJ.
Abstract : We have developed a facile synthesis of 3,3-diphenylpropanamides using Meldrum's acid derivatives as amide coupling components. The in vitro biological evaluation of the title compounds led to the identification of compound 1h, which has good inhibitory activity against T-type calcium channel (IC(50) = 0.83 μM).
|
Inhibition of human ERG
|
Homo sapiens
|
54.95
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.
Year : 2011
Volume : 46
Issue : 2
First Page : 618
Last Page : 630
Authors : Sinha N, Sen S.
Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.
|
Displacement of [3H]methylspiperone from human low affinity Dopamine D2S receptor by competition binding assay
|
Homo sapiens
|
11.7
nM
|
|
Journal : J. Med. Chem.
Title : Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.
Year : 2012
Volume : 55
Issue : 22
First Page : 9735
Last Page : 9750
Authors : Mattsson C, Andreasson T, Waters N, Sonesson C.
Abstract : A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
167.9
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
121.67
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of Na channel (species unknown)
|
None
|
54.0
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 voltage-gated L-type Ca channel (species unknown)
|
None
|
162.0
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 hERG K channel
|
None
|
20.0
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 Cav1.2 current measured using QPatch automatic path clamp system in CHO cells expressing Cav1.2, beta-2 and alpha-2/delta-1 subunits
|
Cricetulus griseus
|
240.0
nM
|
|
Journal : Scientific Reports
Title : MICE models: superior to the HERG model in predicting Torsade de Pointes.
Year : 2013
Volume : 3
First Page : 1
Last Page : 7
Authors : Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Bruening-Wright A, Verducci JS, Brown AM.
Abstract : Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
93.99
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.15
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
25.82
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.15
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
