Category: benzothiophene

Schuster, Daniela published the artcileDevelopment and validation of an in silico P450 profiler based on pharmacophore models, SDS of cas: 40180-04-9, the main research area is Cytochrome P450 inhibitor pharmacophore model enzyme kinetics.

In today’s drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. A part from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P 450 (P 450) enzyme superfamily. e.g. P 450 1A2, P 450 2C9, P 450 2C19, P 450 2D6, and P 450 3A4, contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P 450 family were generated employing the software packages LigandScout and Catalyst. Essential chem. ligand features for substrate and inhibitor activity for all five P 450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P 450 profiling tool that could be used for early ADME estimation of new chem. entities.

Current Drug Discovery Technologies published new progress about Drug discovery. 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, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Liu, Ruifeng published the artcileLocally Weighted Learning Methods for Predicting Dose-Dependent Toxicity with Application to the Human Maximum Recommended Daily Dose, Category: benzothiophene, the main research area is drug toxicity prediction QSAR learning method.

Toxicol. experiments in animals are carried out to determine the type and severity of any potential toxic effect associated with a new lead compound The collected data are then used to extrapolate the effects on humans and determine initial dose regimens for clin. trials. The underlying assumption is that the severity of the toxic effects in animals is correlated with that in humans. However, there is a general lack of toxic correlations across species. Thus, it is more advantageous to predict the toxicol. effects of a compound on humans directly from the human toxicol. data of related compounds However, many popular quant. structure-activity relationship (QSAR) methods that build a single global model by fitting all training data appear inappropriate for predicting toxicol. effects of structurally diverse compounds because the observed toxicol. effects may originate from very different and mostly unknown mol. mechanisms. In this article, we demonstrate, via application to the human maximum recommended daily dose data that locally weighted learning methods, such as k-nearest neighbors, are well suited for predicting toxicol. effects of structurally diverse compounds We also show that a significant flaw of the k-nearest neighbor method is that it always uses a constant number of nearest neighbors in making prediction for a target compound, irresp. of whether the nearest neighbors are structurally similar enough to the target compound to ensure that they share the same mechanism of action. To remedy this flaw, we proposed and implemented a variable number nearest neighbor method. The advantages of the variable number nearest neighbor method over other QSAR methods include (1) allowing more reliable predictions to be achieved by applying a tighter mol. distance threshold and (2) automatic detection for when a prediction should not be made because the compound is outside the applicable domain.

Chemical Research in Toxicology published new progress about Drug screening. 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, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Gomez-Lechon, Maria Jose published the artcileMechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project, COA of Formula: C13H8Cl2O4S, the main research area is development innovative hepatotoxicity LIINTOP project.

The 6th European Framework Program project LIINTOP was specifically raised to optimize and provide established protocols and exptl. in vitro models for testing intestinal and liver absorption, metabolism and toxicity of mols. of pharmacol. interest. It has been focused on some of the most promising existing liver and intestine in vitro models with the aim of further improving their performance and thus taking them to a pre-normative research stage. Regarding the specific area of the liver, a first basic approach was the optimization of in vitro hepatic models and the development and optimization of in vitro approaches for toxicity screening. New advanced technologies have been proposed and developed in order to determine cellular and mol. targets as endpoints of drug exposure. A key issue in the development and optimization of in vitro hepatotoxicity screening methods was the selection of structurally diverse suitable hepatotoxic reference model compounds to be tested. To this end, a number of solid selection criteria were defined (drugs preferably than chem. agents, well-documented hepatotoxicity in man and well-defined mechanism/s of hepatotoxicity, com. available no volatile compounds with unequivocal CAS number and chem. structure), the strategy followed, including all resources consulted, is described and the selected compounds are extensively illustrated.

Toxicology in Vitro published new progress about Drug screening. 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

Haarhoff, Zuzana published the artcileCoupling laser diode thermal desorption with acoustic sample deposition to improve throughput of mass spectrometry-based screening, SDS of cas: 40180-04-9, the main research area is cytochrome P450 inhibition laser diode thermal desorption acoustic deposition; human cytochrome P450 inhibition high throughput screening mass spectrometry; enzyme assays; label-free technologies; liquid handling; mass spectrometry; multiplex assays and technology.

The move toward label-free screening in drug discovery has increased the demand for mass spectrometry (MS)-based anal. Here we investigated the approach of coupling acoustic sample deposition (ASD) with laser diode thermal desorption (LDTD)-tandem mass spectrometry (MS/MS). We assessed its use in a cytochrome P 450 (CYP) inhibition assay, where a decrease in metabolite formation signifies CYP inhibition. Metabolite levels for 3 CYP isoforms were measured as CYP3A4-1′-OH-midazolam, CYP2D6-dextrorphan, and CYP2C9-4′-OH-diclofenac. After incubation, samples (100 nL) were acoustically deposited onto a stainless steel 384-LazWell plate, then desorbed by an IR laser directly from the plate surface into the gas phase, ionized by atm. pressure chem. ionization (APCI), and analyzed by MS/MS. Using this method, we achieved a sample anal. speed of 2.14 s/well, with bioanal. performance comparable to the current online solid-phase extraction (SPE)-based MS method. An even faster readout speed was achieved when postreaction sample multiplexing was applied, where three reaction samples, one for each CYP, were transferred into the same well of the LazWell plate. In summary, LDTD coupled with acoustic sample deposition and multiplexing significantly decreased anal. time to 0.7 s/sample, making this MS-based approach feasible to support high-throughput screening (HTS) assays.

Journal of Biomolecular Screening published new progress about Drug screening. 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, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Koenigs, Luke L. published the artcileElectrospray Ionization Mass Spectrometric Analysis of Intact Cytochrome P450: Identification of Tienilic Acid Adducts to P450 2C9, Computed Properties of 40180-04-9, the main research area is cytochrome P450 tienilate adduct mass spectrometry.

A general scheme for the purification of baculovirus-expressed cytochrome P450s (P450s) from the crude insect cell pastes has been designed which renders the P450s suitable for anal. by high-performance liquid chromatog. (HPLC) electrospray ionization mass spectrometry (ESI-MS). An HPLC/ESI-MS procedure has been developed to analyze small amounts of intact purified P 450 (P450s cam-HT, 1A1, 1A2, 2A6, 2B1, 2C9, 2C9 C175R, 3A4, 3A4-HT) and rat NADPH cytochrome P 450 reductase (P 450 reductase). The exptl. determined and predicted (based on the amino acid sequences) mol. masses (MMs) of the various proteins had identical rank orders. For each individual protein, the difference between the exptl. determined (±SD, based on experiments performed on at least 3 different days) and predicted MMs ranged from 0.002 to 0.035%. Each exptl. determined MM had a standard deviation of less than 0.09% (based on the charge state distribution). Application of this HPLC/ESI-MS technique made the detection of the covalent modification to P 450 2C9 following mechanism-based inactivation by tienilic acid possible. In the absence of glutathione, three P 450 2C9 species were detected that produced ESI mass spectra corresponding to native P 450 2C9 and both a monoadduct and a diadduct of tienilic acid to P 450 2C9. In the presence of glutathione, only native P 450 2C9 and the monoadduct were detected. Based on the observed mass shifts for the P 450 2C9/tienilic acid adducts, a mechanism for the inactivation of P 450 2C9 by tienilic acid is proposed.

Biochemistry published new progress about Molecular weight. 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, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Nakayama, Shintaro published the artcileA zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is idiosyncratic drug toxicity daily dose covalent binding risk assessment.

The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. The authors determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression anal. indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression anal. to create three zones, 30 of 37 tested drugs were located in zones corresponding to their resp. classified safety categories. In conclusion, the authors established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

Drug Metabolism and Disposition published new progress about Agranulocytosis. 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Pogrebnoi, A. A. published the artcileModeling complexes of substrates with cytochrome P450 2C9, Category: benzothiophene, the main research area is modeling substrate cytochrome P450 2C9 algorithm CiS complex.

Complexes of 16 substrates with 2C9 isoform of Cytochrome P 450 complex taken from the PDB database have been modeled using 3D-QSAR algorithm CiS. The arrangement of substrate mols. and the orientation of their reaction centers with respect to the heme in modeled complexes have been analyzed. The orientation of substrate mols. in the model complexes explains the exptl. observed metabolic reactions. The results show that the CiS algorithm is capable of predicting the metabolic pathways of the modeled complexes.

Pharmaceutical Chemistry Journal published new progress about Algorithm (CiS). 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, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Martin, Parthena published the artcileIn vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions, Product Details of C13H8Cl2O4S, the main research area is liver cell fenfluramine norfenfluramine drug interaction; antiepileptics; cytochrome P450; drug transport; drug-drug interactions.

Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood-onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To assess risk of drug interaction affecting pharmacokinetics of FFA and its major metabolite, norfenfluramine (nFFA), we conducted in vitro metabolite characterization, reaction phenotyping, and drug transporter-mediated cellular uptake studies. FFA showed low in vitro clearance in human liver S9 fractions and in intestinal S9 fractions in all three species tested (t1/2 > 120 min). Two metabolites (nFFA and an N-oxide or a hydroxylamine) were detected in human liver microsomes vs. six in dog and seven in rat liver microsomes; no metabolite was unique to humans. Selective CYP inhibitor studies showed FFA metabolism partially inhibited by quinidine (CYP2D6, 48%), phencyclidine (CYP2B6, 42%), and furafylline (CYP1A2, 32%) and, to a lesser extent (<15%), by tienilic acid (CYP2C9), esomeprazole (CYP2C19), and troleandomycin (CYP3A4/5). Incubation of nFFA with rCYP1A2, rCYP2B6, rCYP2C19, and rCYP2D6 resulted in 10%-20% metabolism and no clear inhibition of nFFA metabolism by any CYP-selective inhibitor. Reaction phenotyping showed metabolism of FFA by recombinant human cytochrome P 450 (rCYP) enzymes rCYP2B6 (10%-21% disappearance for 1 and 10μM FFA, resp.), rCYP1A2 (22%-23%), rCYP2C19 (49%-50%), and rCYP2D6 (59%-97%). Neither FFA nor nFFA was a drug transporter substrate. Results show FFA metabolism to nFFA occurs through multiple pathways of elimination. FFA dose adjustments may be needed when administered with strong inhibitors or inducers of multiple enzymes involved in FFA metabolism (e.g., stiripentol). Pharmacology Research & Perspectives published new progress about Anticonvulsants. 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, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Jaladanki, Chaitanya K. published the artcileToxicity Originating from Thiophene Containing Drugs: Exploring the Mechanism using Quantum Chemical Methods, Application In Synthesis of 40180-04-9, the main research area is thiophene drug toxicity quantum chem cytochrome P 450 metabolism.

Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S-oxidation and epoxidation In this work, the mol. level details of the bioinorganic chem. associated with the generation of these competitive reactions are reported. D. functional theory was utilized (i) to explore the mol. mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH- as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the at. level.

Chemical Research in Toxicology published new progress about Aplastic anemia. 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 In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Contrera, Joseph F. published the artcileEstimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose, Computed Properties of 40180-04-9, the main research area is QSAR structure activity relationship mol modeling drug screening.

Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clin. trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clin. trials. The MRDD is an estimated upper dose limit beyond which a drug’s efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicol.) or undesirable pharmacol. effects are observed The NOAEL in test animals is currently used to estimate the safe starting dose in human clin. trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chems. in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topol. descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74-78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of ±10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clin. trials with the addition of a 10-fold safety factor. For non-pharmaceutical chems. any compound-related effect can be considered an undesirable and adverse toxicol. effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.

Regulatory Toxicology and Pharmacology published new progress about Clinical trials. 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, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem