Category: 40180-04-9

Li, Junhao published the artcileEffects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates, COA of Formula: C13H8Cl2O4S, the main research area is mol docking protein structure prediction CYP2C19 water metabolism.

Structure-based prediction of sites of metabolism (SOMs) mediated by cytochrome P450s (CYPs) is of great interest in drug discovery and development. However, protein flexibility and active site water mols. remain a challenge for accurate SOM prediction. CYP2C19 is one of the major drug-metabolizing enzymes and has attracted considerable attention because of its polymorphism and capability of metabolizing ∼7% clin. used drugs. In this study, we systematically evaluated the effects of protein flexibility and active site water mols. on SOM prediction for CYP2C19 substrates. Multiple conformational sampling techniques including GOLD flexible residues sampling, mol. dynamics (MD) and tCONCOORD side-chain sampling were adopted for assessing the influence of protein flexibility on SOM prediction. The prediction accuracy could be significantly improved when protein flexibility was considered using the tCONCOORD sampling method, which indicated that the side-chain conformation was important for accurate prediction. However, the inclusion of the crystallog. or MD-derived water mol.(s) does not necessarily improve the prediction accuracy. Finally, a combination of docking results with SMARTCyp was found to be able to increase the SOM prediction accuracy.

Molecular BioSystems published new progress about Dealkylation. 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

King, Adam M. published the artcileDevelopment of a rapid profiling method for the analysis of polar analytes in urine using HILIC-MS and ion mobility enabled HILIC-MS, Formula: C13H8Cl2O4S, the main research area is urine polar analyte rapid profiling ion mobility HILIC MS; Hydrophilic interaction chromatography; IMS; LC–MS/MS; Metabolic phenotyping.

As large scale metabolic phenotyping is increasingly employed in preclin. studies and in the investigation of human health and disease the current LC-MS/MS profiling methodologies adopted for large sample sets can result in lengthy anal. times, putting strain on available resources. As a result of these pressures rapid methods of untargeted anal. may have value where large numbers of samples require screening. To develop, characterize and evaluate a rapid UHP-HILIC-MS-based method for the anal. of polar metabolites in rat urine and then extend the capabilities of this approach by the addition of IMS to the system. A rapid untargeted HILIC LC-MS/MS profiling method for the anal. of small polar mols. has been developed. The 3.3 min separation used a Waters BEH amide (1 mm ID) anal. column on a Waters Synapt G2-Si Q-Tof enabled with ion mobility spectrometry (IMS). The methodol., was applied to the metabolic profiling of a series of rodent urine samples from vehicle-treated control rats and animals administered tienilic acid. The same separation was subsequently linked to IMS and MS to evaluate the benefits that IMS might provide for metabolome characterization. The rapid HILIC-MS method was successfully applied to rapid anal. of rat urine and found, based on the data generated from the data acquired for the pooled quality control samples analyzed at regular intervals throughout the anal., to be robust. Peak area and retention times for the compounds detected in these samples showed good reproducibility across the batch. When used to profile the urine samples obtained from vehicle-dosed control and those administered tienilic acid the HILIC-MS method detected 3007 mass/retention time features. Anal. of the same samples using HILIC-IMS-MS enabled the detection of 6711 features. Provisional metabolite identification for a number of compounds was performed using the high collision energy MS/MS information compared against the Metlin MS/MS database and, in addition, both calculated and measured CCS values from an exptl. derived CCS database. A rapid metabolic profiling method for the anal. of polar metabolites has been developed. The method has the advantages of speed and both reducing sample and solvent consumption compared to conventional profiling methods. The addition of IMS added an addnl. dimension for feature detection and the identification of metabolites.

Metabolomics published new progress about Homo sapiens. 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, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Gleeson, M. Paul published the artcilePlasma Protein Binding Affinity and Its Relationship to Molecular Structure: An In-silico Analysis, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is plasma protein binding QSAR.

In-silico plasma protein binding (PPB) models have been generated on human and rat inhouse datasets, and on a human dataset from the literature. From the results reported herein, it is apparent that models built on datasets relevant to the chemotypes under investigation in lead optimization programs will perform considerably better in this role than those generated on diverse compounds from the literature. The inhouse human and rat partial least-squares regression (PLS) models have cross-validated q2 values of 0.53 and 0.42 on the training sets, resp. On the independent test and validation sets, they display similar predictive ability, with logK prediction errors of ∼0.5 log units. This compares to ∼0.25 log units variability expected for experiment Given the considerable interspecies PPB differences, the prediction of PPB in one species using measurements in the other is no better than a prediction from an in-silico model generated on that species.

Journal of Medicinal Chemistry published new progress about Homo sapiens. 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

Wu, Guosheng published the artcileCharacterization of Glutathione Conjugates of Duloxetine by Mass Spectrometry and Evaluation of in Silico Approaches to Rationalize the Site of Conjugation for Thiophene Containing Drugs, HPLC of Formula: 40180-04-9, the main research area is glutathione conjugate duloxetine mass spectrometry evaluation site conjugation.

The in vitro bioactivation of the selective serotonin and norepinephrine reuptake inhibitor duloxetine was investigated using liver microsomes and cytosol, expressed glutathione transferase, and recombinant P 450 2D6 and 1A2. In the presence of glutathione, several conjugates were identified and characterized using a combination of direct infusion nanoelectrospray mass spectrometry on an LTQ/Orbitrap and liquid-chromatog. mass spectrometry on a triple quadrupole. Structural characterization of these conjugates revealed that glutathione conjugation occurred on naphthalene rather than on thiophene and likely proceeded via a reactive epoxide intermediate. Experiments with recombinant P450s and the isoform specific inhibitors quinidine and furafylline suggested that both P 450 2D6 and 1A2 were involved in the bioactivation of duloxetine. To explore the utility of in silico approaches to address bioactivation issues, MetaSite and two docking approaches (rigid and induced-fit docking) utilizing publicly available human P 450 crystal structures or a homol. model for P 450 2C19 were used to predict the sites of bioactivation for duloxetine as well as the thiophene containing compounds tienilic acid, suprofen, ticlopidine, methapyrilene, and OSI-930 for which glutathione conjugates on the thiophene moiety have been reported. MetaSite and induced fit docking but not rigid docking correctly predicted that naphthalene rather than thiophene was the preferred site of bioactivation for duloxetine by P 450 2D6. MetaSite predictions were also consistent with literature reports that thiophene was the site of glutathione conjugation for tienilic acid, suprofen, and OSI-930 but not for ticlopidine or methapyrilene. Of the two docking approaches investigated, induced fit docking results were consistent with thiophene as the site of bioactivation for all compounds to which it was applied. In conclusion, our investigation identified the likely bioactivation pathway for duloxetine and demonstrated the utility of in silico approaches MetaSite and induced fit docking to address potential bioactivation liabilities.

Chemical Research in Toxicology published new progress about Homo sapiens. 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Nakayama, Shintaro published the artcileCombination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites, Quality Control of 40180-04-9, the main research area is glutathione trapping covalent binding liver microsome reactive metabolite pharmacokinetics.

Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qual. trapping assay using agents such as [35S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [35S]GSH trapping assay in detecting RMs. We performed CB assays, [35S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds First, we showed that the [35S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [35S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as pos. in the TDI assay to show a high degree of CB irresp. of the result of the [35S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CLint, RMs). The Spearman rank correlation coefficient between the extent of CB and CLint, RMs was 0.77 (p < 0.0001), which was better than that for the formation rates of [35S]GSH adducts. Therefore, we demonstrated that a combination of the [35S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery. Drug Metabolism and Disposition published new progress about Homo sapiens. 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

Yamaoka, Toshikazu published the artcileCharacterization of a highly sensitive and selective novel trapping reagent, stable isotope labeled glutathione ethyl ester, for the detection of reactive metabolites, HPLC of Formula: 40180-04-9, the main research area is reactive metabolite stable isotope glutathione ethyl ester trapping reagent; Bioactivation; Glutathione trapping assay; Idiosyncratic toxicity; Reactive intermediate; Stable isotope.

Glutathione (GSH) trapping assays are widely used to predict the post-marketing risk for idiosyncratic drug reactions (IDRs) in the pharmaceutical industry. Although several GSH derivatives have been introduced as trapping reagents for reactive intermediates, more sensitive and selective reagents are desired to prevent the generation of erroneous results. In this study, stable isotope labeled GSH Et ester (GSHEE-d5) was designed and its detection capability was evaluated. GSHEE-d5 was synthesized and its detection potential was compared with stable isotope labeled GSH ([13C2,15N]GSH) as a reference trapping reagent. The trapping reagents were added to human liver microsomes as a 1:1 mixture with GSHEE or GSH, resp., and incubated with seven IDR pos. drugs and three IDR neg. drugs. The adducts formed between the reagents and reactive metabolites were analyzed by unit resolution mass spectrometer (MS) using isotope pattern-dependent scan with neutral loss filtering. A single-step reaction of GSH and ethanol-d6 produced GSHEE-d5 with a yield of 85%. The GSHEE-d5 assay detected adducts with all seven IDR pos. drugs, and no adducts were detected with the three IDR neg. drugs. In contrast, the [13C2,15N]GSH assay failed to detect adducts with three of the IDR pos. drugs. In the case of diclofenac, the GSHEE-d5 assay showed a 4-times greater signal intensity than the [13C2,15N]GSH assay. GSHEE-d5 enabled the detection of reactive metabolites with greater sensitivity and selectivity than [13C2,15N]GSH. These results demonstrate that GSHEE-d5 would be a useful trapping reagent for evaluating the risk of IDRs with unit resolution MS.

Journal of Pharmacological and Toxicological Methods published new progress about Homo sapiens. 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Peitzman, Steven J. published the artcileTicrynafen and probenecid in hyperuricemic, hypertensive men, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is uricosuria hypertension ticrynafen probenecid; hyperuricemia ticrynafen probenecid.

In a double-blind crossover study of ticrynafen (I) and probenecid (II) [57-66-9], hypertensive, hyperuricemic men completed 12-wk courses of each drug. With a I dose of 125 mg daily, the fall in serum uric acid [69-93-2] was prompt, dramatic, and lasting; it was equal to that after II, 500 or 1000 mg daily. There was a small but significant early weight loss (diuresis) after I but no antihypertensive effect. Twelve days after resuming I for a proposed addnl. extension study 1 patient had acute, reversible bilateral ureteral obstruction, probably caused by sudden urinary uric acid precipitation

Clinical Pharmacology & Therapeutics (St. Louis, MO, United States) published new progress about Hypertension. 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

Varga, Janos M. published the artcileMechanism of allergic cross-reactions. I. Multispecific binding of ligands to a mouse monoclonal anti-DNP IgE antibody, Related Products of benzothiophene, the main research area is antibody drug interaction cross reaction; allergy immediate hypersensitivity antibody ligand; IgE ligand cross reaction.

A recently developed solid-phase binding assay was used to investigate the specificity of ligand binding to a mouse monoclonal anti-dinitrophenyl IgE (I). All DNP-amino acids, that were tested inhibited the binding of the radio-labeled I to DNP covalently attached to polystyrene microplates; however, the concentration for 50% inhibition varied within four orders of magnitude, DNP-L-serine being the most and DNP-L-proline the least potent inhibitor. In addition to DNP analogs, a large number of drugs and other compounds were tested for their ability to compete with DNP for the binding site of I. At the concentration used for screening, 59% of compounds had no significant inhibition; 19% inhibited the binding of I more than 50%. Several families of compounds (tetracyclines, polymyxins, phenothiazines, salicylates, and quinones) that were effective competitors were found. Within these families, changes in the functional groups attached to the family stem had major effects on the affinity of ligand binding. The occurrence frequencies of interactions of ligands with I is in good agreement with the semi-empirical model for multispecific antibody-ligand interactions.

Molecular Immunology published new progress about Antibiotics. 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, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Mironneau, J. published the artcileEffect of tienilic acid on the electromechanical properties of vascular smooth muscles in normotensive and spontaneously hypertensive rats, Category: benzothiophene, the main research area is tienilate blood vessel contractility; hypertension vascular muscle tienilic acid.

The membrane potential and ionic currents of smooth muscle strips of the portal vein were similar in normotensive rats (WKY) and spontaneously hypertensive rats (SHR). The maximal rate of rise of isometric contractions was increased in SHR as compared with WKY rats, and the smooth muscle membrane of SHR rats was more sensitive to noradrenaline  [51-41-2], angiotensin II  [11128-99-7], and prostaglandin E1  [745-65-3]. Tienilic acid (TA) [40180-04-9] depressed both action potential and contraction amplitudes in both WKY and SHR preparations The inward Ca current was reduced, but the K current was not. Chronic administration of TA to SHR (6 mo) suppressed the increased sensitivity to noradrenaline, angiotensin II, and prostaglandin E1. TA apparently acts primarily on the plasma surface of vascular smooth muscle by reducing the inward Ca current. In this way, it may decrease both cytoplasmic Ca concentration and vascular contractility in SHR.

Journal of Cardiovascular Pharmacology published new progress about Portal vein. 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

Lewis, David F. V. published the artcileHomology modeling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity, COA of Formula: C13H8Cl2O4S, the main research area is cytochrome P450 xenobiotic metabolism substrate selectivity.

Mol. modeling of human cytochrome P 450 (CYP) isoforms is described, based on amino acid sequence homol. with a unique bacterial P 450 (CYP102) of known crystal structure. It is found that for the human hepatic P450s involved in the metabolism of xenobiotics, ie. CYP1A2, CYP1A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, there is a satisfactory agreement between specific substrate characteristics and topog. features of the putative active sites, including complementarity with key amino acid residues in the P 450 hem environments. A combination of homol. model interactions with substrates and certain mol. properties of the compounds themselves provides a methodol. for the evaluation of potential P 450 selectivity in new chem. entities (NCEs).

Experimental and Toxicologic Pathology published new progress about Xenobiotics. 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