Category: 40180-04-9

Huang, Tao published the artcilePrediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles, Quality Control of 40180-04-9, the main research area is xenobiotic drug discovery toxicity prognosis.

More and more people are concerned by the risk of unexpected side effects observed in the later steps of the development of new drugs, either in late clin. development or after marketing approval. To reduce the risk of the side effects, it is important to look out for the possible xenobiotic responses at an early stage. The authors attempt such an effort through a prediction by assuming that similarities in microarray profiles indicate shared mechanisms of action and/or toxicol. responses among the chems. being compared. A large time course microarray database derived from livers of compound-treated rats with thirty-four distinct pharmacol. and toxicol. responses were studied. The mRMR (Min.-Redundancy-Maximum-Relevance) method and IFS (Incremental Feature Selection) were used to select a compact feature set (141 features) for the reduction of feature dimension and improvement of prediction performance. With these 141 features, the Leave-one-out cross-validation prediction accuracy of first order response using NNA (Nearest Neighbor Algorithm) was 63.9%. The authors’ method can be used for pharmacol. and xenobiotic responses prediction of new compounds and accelerate drug development.

PLoS One published new progress about Basophil. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Saiakhov, Roustem published the artcileEffectiveness of CASE Ultra Expert System in Evaluating Adverse Effects of Drugs, COA of Formula: C13H8Cl2O4S, the main research area is quant structure activity relationship drug withdrawal toxicity; Adverse effects; CASE Ultra; Expert systems; QSAR; Risk assessment; in silico.

Purpose of this pilot study is to test the QSAR expert system CASE Ultra for adverse effect prediction of drugs. 870 drugs from the SIDER adverse effect dataset were tested using CASE Ultra for carcinogenicity, genetic, liver, cardiac, renal and reproductive toxicity. 47 drugs that were withdrawn from market since the 1950s were also evaluated for potential risks using CASE Ultra and compared them with the actual reasons for which the drugs were recalled. For the whole SIDER test set (n=870), sensitivity and specificity of the carcinogenicity predictions are 66.67 % and 82.17 % resp.; for liver toxicity: 78.95 %, 78.50 %; cardiotoxicity: 69.07 %, 57.57 %; renal toxicity: 46.88 %, 67.90 %; and reproductive toxicity: 100.00 %, 61.10 %. For the SIDER test chems. not present in the training sets of the models, sensitivity and specificity of carcinogenicity predictions are 100.00 % and 88.89 % resp. (n=404); for liver toxicity: 100.00 %, 51.33 % (n=115); cardiotoxicity: 100.00 %, 20.45 % (n=94); renal toxicity: 100.00 %, 45.54 % (n=115); and reproductive toxicity: 100.00 %, 48.57 % (n=246). CASE Ultra correctly recognized the relevant toxic effects in 43 out of the 47 withdrawn drugs. It predicted all 9 drugs that were not part of the training set of the models, as unsafe.

Molecular Informatics published new progress about Behavior. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Bell, Leslie published the artcileEvaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery, COA of Formula: C13H8Cl2O4S, the main research area is cytochrome P450 drug discovery fluorescence mass spectrometry bioassay.

The potential for metabolism-related drug-drug interactions by new chem. entities is assessed by monitoring the impact of these compounds on cytochrome P 450 (CYP) activity using well-characterized CYP substrates. The conventional gold standard approach for in vitro evaluation of CYP inhibitory potential uses pooled human liver microsomes (HLM) in conjunction with prototypical drug substrates, often quantified by LC-MS/MS. However, fluorescent CYP inhibition assays, which use recombinantly expressed CYPs and fluorogenic probe substrates, have been employed in early drug discovery to provide low-cost, high-throughput assessment of new chem. entities. Despite its greatly enhanced throughput, this approach has been met with mixed success in predicting the data obtained with the conventional gold standard approach (HLM+LC-MS). The authors find that the predictivity of fluorogenic assays for the major CYP isoforms 3A4 and 2D6 may depend on the quality of the test compounds Although the structurally more optimized marketed drugs yielded acceptable correlations between the fluorogenic and HLM+LC-MS/MS assays for CYPs 3A4, 2D6, and 2C9 (r2 = 0.5-0.7; p < 0.005), preoptimization, early discovery compounds yielded poorer correlations (r2 ≤ 0.2) for 2 of these major isoforms, CYPs 3A4 and 2D6. Potential reasons for the observed differences are discussed. Journal of Biomolecular Screening published new progress about Bioassay. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Gershbein, Leon L. published the artcileAction of drugs and chemical agents on rat liver regeneration, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is liver regeneration chem drug; hormone liver regeneration; vaccine liver regeneration.

A large number (> 270) of drugs, chems., and other agents were tested for their effects on the regeneration of liver in hepatectomized rats. Seven anticonvulsants, 4 antiinflammatory drugs, 4 sedatives-hypnotics, the antipyretic-analgesic aminopyrine  [58-15-1], the antifungal griseofulvin  [126-07-8], a uricosuric, a muscle relaxant, a hydrocholeretic, an antihypertensive, and a thyroid inhibitor were hepatotrophic. Most the remaining drugs were inactive in this screening, whereas a few suppressed liver regeneration.

Drug and Chemical Toxicology (1977) published new progress about Analgesics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Bala, Snega published the artcileMolecular characterization and identification of copper transport in Wilson disease, Quality Control of 40180-04-9, the main research area is ATP7B diuretic copper mol docking Wilson disease.

Wilson’s disease or hepatolenticular degeneration in an autosomal recessive genetic disorder in which copper accumulates in tissues. The condition is due to mutations in Wilson disease protein (ATP7B). A special feature of WD is that medical therapy is used to treat presymptomatic as well as symptomatic individuals, and hepatic transplantation can reverse the metabolic abnormality. In the present research work, an attempt has been made to map the binding site residues of ATP7B protein (receptor). The 3D structure of the monomeric protein was not yet not been exptl. elucidated for which the theor. structure was determined by homol. modeling using 2UVC as template and the structure was validated and refined by SAVS and MODELLER. The generated 3D structure of ATP7B protein was solvated at 310k and energy minimized using Gromacs. Similarly, 2D structures of several diuretic compounds were retrieved, refined and energy minimized using Arguslab software. The diuretic compounds were then subjected to analyze their adsorption, distribution, metabolism, excretion and their toxicity properties. This anal. was done using the online server PREADME/TOX. The protein-ligand interactions between the ATP7B protein and the diuretic compounds were analyzed using Autodock – PyRx and the docking models were visualized and analyzed by PyMol. Based on the output of the docking models and the binding energies the best lead compound was determined which can be used for fighting against the Wilson disease.

Journal of Computational Methods in Molecular Design published new progress about Asteraceae. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Takakusa, Hideo published the artcileMarkers of electrophilic stress caused by chemically reactive metabolites in human hepatocytes, Quality Control of 40180-04-9, the main research area is drug hepatotoxicity reactive metabolite heme oxygenase biomarker.

The metabolic activation of a drug to an electrophilic reactive metabolite and its covalent binding to cellular macromols. is considered to be involved in the occurrence of idiosyncratic drug toxicity (IDT). As a cellular defense system against oxidative and electrophilic stress, phase II enzymes are known to be induced through a Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2/antioxidant response element system. We presumed that it is important for the risk assessment of drug-induced hepatotoxicity and IDTs to observe the biol. responses evoked by exposure to reactive metabolites, and then investigated the mRNA induction profiles of phase II enzymes in human hepatocytes after exposure to problematic drugs associated with IDTs, such as ticlopidine, diclofenac, clozapine, and tienilic acid, as well as safe drugs such as levofloxacin and caffeine. According to the results, the problematic drugs exhibited inductive effects on heme oxygenase 1 (HO-1), which contrasted with the safe drugs; therefore, the induction of HO-1 mRNA seems to be correlated with the occurrence of drug toxicity, including IDT caused by electrophilic reactive metabolites. Moreover, glutathione-depletion and cytochrome P 450-inhibition experiments have shown that the observed HO-1 induction was triggered by the electrophilic reactive metabolites produced from the problematic drugs through P 450-mediated metabolic bioactivation. Taken together with our present study, this suggests that HO-1 induction in human hepatocytes would be a good marker of the occurrence of metabolism-based drug-induced hepatotoxicity and IDT caused by the formation of electrophilic reactive metabolites.

Drug Metabolism and Disposition published new progress about Biomarkers. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Cavasin, Anna Theresa published the artcileReliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is low energy conformer gas phase water.

Prediction of compound properties from structure via quant. structure-activity relationship and machine-learning approaches is an important computational chem. task in small-mol. drug research. Though many such properties are dependent on three-dimensional structures or even conformer ensembles, the majority of models are based on descriptors derived from two-dimensional structures. Here we present results from a thorough benchmark study of force field, semiempirical, and d. functional methods for the calculation of conformer energies in the gas phase and water solvation as a foundation for the correct identification of relevant low-energy conformers. We find that the tight-binding ansatz GFN-xTB shows the lowest error metrics and highest correlation to the benchmark PBE0-D3(BJ)/def2-TZVP in the gas phase for the computationally fast methods and that in solvent OPLS3 becomes comparable in performance. MMFF94, AM1, and DFTB+ perform worse, whereas the performance-optimized but far more expensive functional PBEh-3c yields energies almost perfectly correlated to the benchmark and should be used whenever affordable. On the basis of our findings, we have implemented a reliable and fast protocol for the identification of low-energy conformers of drug-like mols. in water that can be used for the quantification of strain energy and entropy contributions to target binding as well as for the derivation of conformer-ensemble-dependent mol. descriptors.

Journal of Chemical Information and Modeling published new progress about Conformers. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Hicks, Michael B. published the artcileAssessment of coulometric array electrochemical detection coupled with HPLC-UV for the absolute quantitation of pharmaceuticals, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is coulometry electrochem detection liquid chromatog pharmaceutical.

The use of a coulometric array detector in tandem with HPLC-UV was evaluated for the absolute quantitation of pharmaceutical compounds without standards, an important capability gap in contemporary pharmaceutical research and development. The high-efficiency LC flow-through electrochem. detector system allows for the rapid evaluation of up to 16 different potentials, aiding in the identification and quantitation of electrochem. reactive species. By quantifying the number of electrons added or removed from an analyte during its passage through the detector, the number of moles of the analyte can be established. Herein we demonstrate that mols. containing common electroactive functional groups (e.g. anilines, phenols, parabens and tertiary alkyl amines) can in some cases be reliably quantified in HPLC-EC-UV without the need for authentic standards Furthermore, the multichannel nature of the CoulArray detector makes it well suited for optimizing the conditions for electrochem. reaction, allowing the impact of changes in potential, flow rate, temperature and pH to be conveniently studied. The electrochem. oxidation of albacivir, zomepirac, diclofenac, rosiglitazone and several other marketed drugs resulted in large linear ranges, predictable recoveries and excellent quantitation using the total moles of electrons and back-calculating using Faraday’s law. Importantly, we observed several instances where subtle structural changes within a given class of mols. (e.g. aromatic ring isomers) led to unanticipated changes in electrochem. behavior. Consequently, some care should be taken when applying the technique to the routine quantitation of compound libraries where standards are not available.

Analyst (Cambridge, United Kingdom) published new progress about Coulometry. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

McGinnity, Dermot F. published the artcileEvaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes, Synthetic Route of 40180-04-9, the main research area is drug cytochrome P450 inhibition human hepatocyte.

Primary human hepatocytes in culture are commonly used to evaluate cytochrome P 450 induction via an enzyme activity endpoint. However, other processes can confound data interpretation. To this end, the impact of time-dependent P 450 inhibition in this system was evaluated. Using a substrate-cassette approach, P 450 activities were determined after incubation with the prototypic inhibitors tienilic acid (CYP2C9), erythromycin, troleandomycin, and fluoxetine (CYP3A4). Kinetic anal. of enzyme inactivation in hepatocytes was used to describe the effect of these time-dependent inhibitors and derive the inhibition parameters kinact and Kl, which generally were in good agreement with the values derived using recombinant P450s and human liver microsomes (HLMs). Tienilic acid selectively inhibited CYP2C9-dependent diclofenac 4′-hydroxylation activity, and erythromycin, troleandomycin, and fluoxetine inhibited CYP3A4-dependent midazolam 1′-hydroxylation in a time- and concentration-dependent manner. Fluoxetine also inhibited CYP2C19-dependent S-mephenytoin 4′-hydroxylation in a time- and concentration-dependent manner in hepatocytes, HLMs, and recombinant CYP2C19 (Kl 0.4 μM and kinact 0.5 min-1). As expected, the effect of fluoxetine on CYP2D6 in hepatocytes was consistent with potent yet reversible inhibition. A very weak time-dependent CYP2C9 inhibitor (AZ1, a proprietary AstraZeneca compound; Kl 30 μM and kinact 0.02 min-1) effectively abolished CYP2C9 activity over 24 h at low (micromolar) concentrations in primary cultured human hepatocytes. This work demonstrates that caution is warranted in the interpretation of enzyme induction studies with metabolically stable, weak time-dependent inhibitors, which may have dramatic inhibitory effects on P 450 activity in this system. Therefore, in addition to enzyme activity, mRNA and/or protein levels should be measured to fully evaluate the P 450 induction potential of a drug candidate.

Drug Metabolism and Disposition published new progress about Hepatocyte. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Cruz-Monteagudo, Maykel published the artcileComputational chemistry approach for the early detection of drug-induced idiosyncratic liver toxicity, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is hepatotoxicity drug computational chem QSAR.

Idiosyncratic drug toxicity (IDT), considered as a toxic host-dependent event, with an apparent lack of dose response relationship, is usually not predictable from early phases of clin. trials, representing a particularly confounding complication in drug development. Albeit a rare event (usually <1/5000), IDT is often life threatening and is one of the major reasons new drugs never reach the market or are withdrawn post marketing. Computational methodologies, like the computer-based approach proposed in the present study, can play an important role in addressing IDT in early drug discovery. We report for the first time a systematic evaluation of classification models to predict idiosyncratic hepatotoxicity based on linear discriminant anal. (LDA), artificial neural networks (ANN), and machine learning algorithms (OneR) in conjunction with a 3D mol. structure representation and feature selection methods. These modeling techniques (LDA, feature selection to prevent over-fitting and multicollinearity, ANN to capture nonlinear relationships in the data, as well as the simple OneR classifier) were found to produce QSTR models with satisfactory internal cross-validation statistics and predictivity on an external subset of chems. More specifically, the models reached values of accuracy/sensitivity/specificity over 84%/78%/90%, resp. in the training series along with predictivity values ranging from ca. 78 to 86% of correctly classified drugs. An LDA-based desirability anal. was carried out in order to select the levels of the predictor variables needed to trigger the more desirable drug, i.e. the drug with lower potential for idiosyncratic hepatotoxicity. Finally, two external test sets were used to evaluate the ability of the models in discriminating toxic from nontoxic structurally and pharmacol. related drugs and the ability of the best model (LDA) in detecting potential idiosyncratic hepatotoxic drugs, resp. The computational approach proposed here can be considered as a useful tool in early IDT prognosis. Journal of Computational Chemistry published new progress about Algorithm. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem