Day: November 16, 2022

Chen, Jinjin published the artcileTransition-metal-free selective pyrimidines and pyridines formation from aromatic ketones, aldehydes and ammonium salts, Category: benzothiophene, the main research area is aryl methylketone arylaldehyde ammonium acetate sodium periodate tandem multicomponent; triarylpyrimidine preparation; acetophenone benzaldehyde ammonium iodide three component cyclocondensaton; triphenylpyridine preparation.

An efficient synthesis of pyrimidines and pyridines was developed from readily available aromatic ketones, aldehydes and ammonium salts under transition-metal-free conditions. In this strategy, ammonium salts were used as nitrogen sources and only water was generated as a nontoxic byproduct. A catalytic amount of NaIO4 played an important role in the selectivity control, whereas substituted pyridines were dominantly formed in its absence.

Green Chemistry published new progress about Aldol condensation. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Iwamura, Atsushi published the artcileCYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay, Application In Synthesis of 40180-04-9, the main research area is cytochrome CYP2C9 drug metabolism losartan hepatotoxicity adenovirus vector bioassay.

Drug-induced hepatotoxicity is a major problem in drug development, and reactive metabolites generated by cytochrome P 450s are suggested to be one of the causes. CYP2C9 is one of the major enzymes in hepatic drug metabolism In the present study, we developed a highly sensitive cell-based screening system for CYP2C9-mediated metabolic activation using an adenovirus vector expressing CYP2C9 (AdCYP2C9). Human hepatocarcinoma HepG2 cells infected with our constructed AdCYP2C9 for 2 days at multiplicity of infection 10 showed significantly higher diclofenac 4′-hydroxylase activity than human hepatocytes. AdCYP2C9-infected cells were treated with several hepatotoxic drugs, resulting in a significant increase in cytotoxicity by treatment with losartan, benzbromarone, and tienilic acid. Metabolic activation of losartan by CYP2C9 has never been reported, although the metabolic activations of benzbromarone and tienilic acid have been reported. To identify the reactive metabolites of losartan, the semicarbazide adducts of losartan were investigated by liquid chromatog.-tandem mass spectrometry. Two CYP2C9-specific semicarbazide adducts of losartan (S1 and S2) were detected. S2 adduct formation suggested that a reactive metabolite was produced from the aldehyde metabolite E3179, but a possible metabolite from S1 adduct formation was not produced via E3179. In conclusion, a highly sensitive cell-based assay to evaluate CYP2C9-mediated metabolic activation was established, and we found for the first time that CYP2C9 is involved in the metabolic activation of losartan. This cell-based assay system would be useful for evaluating drug-induced cytotoxicity caused by human CYP2C9.

Drug Metabolism and Disposition published new progress about Adenoviral vectors. 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

Coen, Muireann published the artcileComparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer, COA of Formula: C13H8Cl2O4S, the main research area is NMR metabonomic investigation metabolic phenotype tienilate isomer.

An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clin. chem. and histopathol. analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathol. analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post-treatment correlating with the histopathol. and clin. chem. evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacol. and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity.

Chemical Research in Toxicology published new progress about Adaptation, animal. 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

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

Rastogi, Gaurav K. published the artcileCu(I)/Fe(III) promoted dicarbonylation of aminopyrazole via oxidative C-H coupling with methyl ketones, COA of Formula: C6H6OS, the main research area is aminopyrazole methyl ketone copper iron dicarbonylation oxidative coupling catalyst; diketone aminopyrazole preparation.

Cu(I)/Fe(III) promoted C4-dicarbonylation of 5-aminopyrazole is developed. The strategy involved radical triggered direct oxidative coupling of 5-aminopyrazoles with Me ketones using aerial oxygen as a source of oxygen in newly generated carbonyl group. CuI is used as catalyst and FeCl3·6H2O is used as additive and the reaction proceeded at 120 °C in DMSO for 9-12 h. It is found that use of Cu(II) catalyst gives the thiomethylated product by reacting with DMSO instead of oxidative coupling. A plausible mechanism is also given.

Tetrahedron Letters published new progress about C-H bond activation. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, COA of Formula: C6H6OS.

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

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

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

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

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