Category: 40180-04-9

Prandota, J. published the artcileEffect of tienilic acid (Diflurex) on the binding of 14C-warfarin to human plasma proteins, Product Details of C13H8Cl2O4S, the main research area is tienilate warfarin binding albumin.

Tienilic acid (Diflurex) (I) [40180-04-9], a new diuretic with a chem. structure close to that of ethacrynic acid, displaced significant amounts of warfarin (II) [81-81-2] from human albumin 2 g/L in vitro by a competitive mechanism. No such interaction was observed with physiol. concentrations of human albumin or with human plasma. Because excessive hypoprothrombinemia and hemorrhage were reported in vivo when I was added to oral coumarin anticoagulant therapy, it is advised to use another diuretic if necessary.

International Journal of Clinical Pharmacology, Therapy and Toxicology published new progress about Blood serum albumins. 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

Plessas, C. published the artcileBinding of tienilic acid (Diflurex) to human plasma proteins and erythrocytes, COA of Formula: C13H8Cl2O4S, the main research area is tienilic acid protein binding; erythrocyte tienilic acid binding.

The binding of SKF-62698 (tienilic acid)(Diflurex)(I) [40180-04-9], a new antihypertensive agent with diuretic and uricosuric properties, to human plasma proteins, pure protein fractions, erythrocytes, as well as the effect of heparin [9005-49-6] on the degree of protein binding were measured. Different amounts of I (1 to 1000 μg) were incubated with 1 mL of either human plasma or phosphate buffer M/15 (pH 7.4), containing 47 mg of albumin, at 37° for 2 h. The degree of binding of I to plasma proteins and albumin, at plasma concentration (1-30 μg/mL) of the drug at therapeutic doses, was 99.4-98.5 and 95.8-94.2%, resp. In the case of albumin, a Scatchard plot showed 2 classes of binding sites (M1 = 0.5, K1 = 6.3 × 104/M; M2 = 8, K2 = 2.8 × 103/M). After incubation of 10 μg of drug with 8 mg of α-globulins, 8 mg of β-globulins or 7.4 mg of γ-globulins at 37°, pH 7.4 and ultrafiltration, the degree of binding was 83%, 44%, and 44%, resp. The distribution of I between erythrocytes and plasma ranges between 0.11-0.17 for concentrations of 1 to 15 μg/mL and between 0.17-0.10 for concentrations of 15 to 30 μg/mL under different exptl. conditions, heparin had no effect on the degree of binding of I to plasma proteins.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Blood serum albumins. 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

Prandota, J. published the artcileBinding of tienilic acid (Diflurex) to human serum albumin and to plasma of normal subjects and uremic patients, Quality Control of 40180-04-9, the main research area is tienilate binding plasma protein uremic; serum albumin tienilate binding uremic.

The binding of tienilic acid (TA)(I) [40180-04-9], a new diuretic, to human serum albumin (HSA) and to the plasma of uremic patients under treatment with hemodialysis was measured. At a total concentration of 4.5 μg/mL (expected therapeutic concentration), the unbound fraction of TA to 4% HSA and to normal plasma was 0.49% and 0.6%, resp. The degree of binding was approx. the same from 0.5 to 132 μg/mL of total drug concentration The free fraction of TA increased about 2-fold when total concentration of the drug increased from 0.5 to 192 μg/mL. TA has 2 classes of binding sites. The effect of ionic strength and pH on the binding of TA to HSA indicate that the drug is bound mainly by hydrophobic interaction. Acetylsalicylic acid (300 μg/mL), bilirubin (10 mg%), and palmitic acid (2:1 molar ratio with HSA) decreased TA binding. Reduced drug plasma protein binding was observed in uremic patients. No correlation was found between the unbound fraction of TA and the uremic serum albumin, creatinine, or blood urea concentrations Following an i.v. injection of heparin [9005-49-6], the free fraction of TA in uremic plasma rose from 1.7% to 4.5% after 10 min. of hemodialysis. This could be explained, at least partially, by the increased uremic plasma free fatty acids to albumin molar ratio.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Blood serum albumins. 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

Kaserer, Teresa published the artcileProspective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is virtual drug screening COX inhibitors pharmacophore mol modeling; 2D similarity-based search; Cyclooxygenase; Docking; Method comparison; Pharmacophore modeling; Shape-based modeling.

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then addnl. predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biol. activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true pos. and true neg. hits, and hitlist composition Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.

European Journal of Medicinal Chemistry published new progress about Computer application. 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

Grimm, Scott W. published the artcileThe conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the Pharmaceutical Research and Manufacturers of America, Synthetic Route of 40180-04-9, the main research area is review conduct drug metabolizing.

Time-dependent inhibition (TDI) of cytochrome P 450 enzymes caused by new mol. entities (NMEs) is of concern because such compounds can be responsible for clin. relevant drug-drug interactions (DDI). Although the biochem. underlying mechanism-based inactivation (MBI) of P 450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clin. DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.

Drug Metabolism and Disposition published new progress about Drug bioavailability. 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

Ma, Chang-Ying published the artcilePrediction models of human plasma protein binding rate and oral bioavailability derived by using GA-CG-SVM method, Synthetic Route of 40180-04-9, the main research area is SVM genetic algorithm protein binding pharmacokinetics.

In this study, support vector machine (SVM) method combined with genetic algorithm (GA) for feature selection and conjugate gradient (CG) method for parameter optimization (GA-CG-SVM), has been employed to develop prediction models of human plasma protein binding rate (PPBR) and oral bioavailability (BIO). The advantage of the GA-CG-SVM is that it can deal with feature selection and SVM parameter optimization simultaneously. Five-fold cross-validation as well as independent test set method were used to validate the prediction models. For the PPBR, a total of 692 compounds were used to train and test the prediction model. The prediction accuracy by means of 5-fold cross-validation is 86% and that for the independent test set (161 compounds) is 81%. These accuracies are markedly higher over that of the best model currently available in literature. The number of descriptors selected is 29. For the BIO, the training set is composed of 690 compounds and external 76 compounds form an independent validation set. The prediction accuracy for the training set by using 5-fold cross-validation and that for the independent test set are 80% and 86%, resp., which are better than or comparable to those of other classification models in literature. The number of descriptors selected is 25. For both the PPBR and BIO, the descriptors selected by GA-CG method cover a large range of mol. properties which imply that the PPBR and BIO of a drug might be affected by many complicated factors.

Journal of Pharmaceutical and Biomedical Analysis published new progress about Drug bioavailability. 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

Flora, Darcy R. published the artcileDevelopment of an in vitro system with human liver microsomes for phenotyping of CYP2C9 genetic polymorphisms with a mechanism-based inactivator, Synthetic Route of 40180-04-9, the main research area is cytochrome genetic polymorphism phenotype liver microsome tienilic acid.

Polymorphisms in cytochrome P 450 enzymes can significantly alter the rate of drug metabolism, as well as the extent of drug-drug interactions. Individuals who homozygotically express the CYP2C9*3 allele (I359L) of CYP2C9 exhibit ∼70 to 80% reductions in the oral clearance of drugs metabolized through this pathway; the reduction in clearance is ∼40 to 50% for heterozygotic individuals. Although these polymorphisms result in a decrease in the activity of individual enzyme mols., we hypothesized that decreasing the total number of active enzyme mols. in an in vitro system (CYP2C9*1/*1 human liver microsomes) by an equivalent percentage could produce the same net change in overall metabolic capacity. To this end, the selective CYP2C9 mechanism-based inactivator tienilic acid was used to reduce irreversibly the total CYP2C9 activity in human liver microsomes. Tienilic acid concentrations were effectively titrated to produce microsomal preparations with 43 and 73% less activity, mimicking the CYP2C9*1/*3 and CYP2C9*3/*3 genotypes, resp. With probe substrates specific for other major cytochrome P 450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), no apparent changes in the rate of metabolism were noted for these enzymes after the addition of tienilic acid, which suggests that this model is selective for CYP2C9. In lieu of using rare human liver microsomes from CYP2C9*1/*3 and CYP2C9*3/*3 individuals, a tienilic acid-created knockdown in human liver microsomes may be an appropriate in vitro model to determine CYP2C9-mediated metabolism of a given substrate, to determine whether other drug-metabolizing enzymes may compensate for reduced CYP2C9 activity, and to predict the extent of genotype-dependent drug-drug interactions.

Drug Metabolism & Disposition published new progress about Genetic polymorphism. 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

Croft, Mary Ann published the artcileEffect of ticrynafen on aqueous humor dynamics in monkeys, Quality Control of 40180-04-9, the main research area is ticrynafen aqueous humor glaucoma.

Objective: To determine the effect of ticrynafen, a non-sulfhydryl-reactive compound similar to ethacrynic acid, on outflow facility in normotensive monkey eyes and on intraocular pressure (IOP) in monkey eyes with laser-induced glaucoma. Methods: In normotensive eyes, facility (perfusion) was measured shortly before and after bolus or exchange intracameral infusion of ticrynafen or vehicle in opposite eyes, and 3.5 to 4.5 h after 5 days of twice-daily 2% ticrynafen or vehicle ointment. In glaucomatous eyes, baseline and vehicle diurnal IOP curves were established, 2% ticrynafen ointment was given twice daily for 5 days, and IOP was measured immediately before and 0.5 to 6 h after each morning treatment. Results: In normotensive eyes, exchange 2-mL infusion of 0.2-, 1-, or 4-mmol/L ticrynafen increased facility by 33% ± 6% (mean ± SEM), 73% ± 18%, and 60% ± 11%, resp. Day 5 posttreatment facility was higher in the ticrynafen group than in controls by 28% ± 9%. In glaucomatous eyes, maximum IOP decline, from approx. 35 mm Hg, was 7.5 ± 2.0 mm Hg on day 4 and 9.8 ± 2.4 mm Hg on day 5 of twice-daily ticrynafen treatment. Conclusion: The facility-increasing, IOP-lowering action of ticrynafen, ethacrynic acid, and derivatives may not depend entirely on sulfhydryl reactivity. Clin. Relevance: Whether such drugs as ethacrynic acid and ticrynafen prove valuable for glaucoma therapy, at the least they are useful probes to study aqueous outflow mechanisms.

Archives of Ophthalmology (Chicago) published new progress about Antiglaucoma agents. 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

Hampel, Philip published the artcileAzosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B, Related Products of benzothiophene, the main research area is Xenopus NKCC1A NKCC1B azosemide bumetanide sodium potassium chloride cotransporter.

The Na+-K+-2Cl- cotransporter NKCC1 plays a role in neuronal Cl- homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main variants of NKCC1 have been identified: a full-length NKCC1 transcript (NKCC1A) and a shorter splice variant (NKCC1B) that is particularly enriched in the brain. The loop diuretic bumetanide is often used to inhibit NKCC1 in brain disorders, but only poorly crosses the blood-brain barrier. We determined the sensitivity of the two human NKCC1 splice variants to bumetanide and various other chem. diverse loop diuretics, using the Xenopus oocyte heterologous expression system. Azosemide was the most potent NKCC1 inhibitor (IC50s 0.246 M for hNKCC1A and 0.197μM for NKCC1B), being about 4-times more potent than bumetanide. Structurally, a carboxylic group as in bumetanide was not a prerequisite for potent NKCC1 inhibition, whereas loop diuretics without a sulfonamide group were less potent. None of the drugs tested were selective for hNKCC1B vs. hNKCC1A, indicating that loop diuretics are not a useful starting point to design NKCC1B-specific compounds Azosemide was found to exert an unexpectedly potent inhibitory effect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide.

Scientific Reports published new progress about Blood-brain barrier. 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

Lewis, D. F. V. published the artcileMolecular modeling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed mutagenesis experiments in the CYP2C subfamily, HPLC of Formula: 40180-04-9, the main research area is CYP2C subfamily enzyme mol modeling; cytochrome P450 2C subfamily mol modeling.

The results of mol. modeling of human CYP2C isoenzymes, CYP2C9 and CYP2C19, are reported based on an alignment with a bacterial form of the enzyme, CYP102. The three-dimensional structures of the CYP2C enzymes are consistent with known exptl. evidence from site-directed mutagenesis, antibody recognition and regiospecificity of substrate metabolism The variations in substrate specificity between CYP2C9 and CYP2CI9 can be rationalized in terms of single amino acid residue changes within the putative active site region, of which I99H appears to be the most significant.

Xenobiotica published new progress about Electrostatic force. 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