Day: November 17, 2022

Darnell, Malin published the artcileSignificantly Different Covalent Binding of Oxidative Metabolites, Acyl Glucuronides, and S-Acyl CoA Conjugates Formed from Xenobiotic Carboxylic Acids in Human Liver Microsomes, Related Products of benzothiophene, the main research area is metabolite acyl glucuronide xenobiotic human liver microsome.

Xenobiotic carboxylic acids may be metabolized to oxidative metabolites, acyl glucuronides, and/or S-acyl-CoA thioesters (CoA conjugates) in vitro, e.g., in hepatocytes, and in vivo. These metabolites can potentially be reactive species and bind covalently to tissue proteins and are generally considered to mediate adverse drug reactions in humans. Acyl glucuronide metabolites have been the focus of reactive metabolite research for decades, whereas drug-CoA conjugates, which have been shown to be up to 40-70 times more reactive, have been given much less attention. In an attempt to dissect the contribution of different pathways to covalent binding, we utilized human liver microsomes supplemented with NADPH, uridine 5′-diphosphoglucuronic acid (UDPGA), or CoA to evaluate the reactivity of each metabolite sep. Seven carboxylic acid drugs were included in this study. While ibuprofen and tolmetin are still on the market, ibufenac, fenclozic acid, tienilic acid, suprofen, and zomepirac were stopped before their launch or withdrawn. The reactivities of the CoA conjugates of ibuprofen, ibufenac, fenclozic acid, and tolmetin were higher compared to those of their corresponding oxidative metabolites and acyl glucuronides, as measured by the level of covalent binding to human liver microsomal proteins. The highest covalent binding was observed for ibuprofenyl-CoA and ibufenacyl-CoA, to levels of 1000 and 8600 pmol drug eq/mg protein, resp. In contrast and in agreement with the proposed P 450-mediated toxicity for these drug mols., the reactivities of oxidative metabolites of suprofen and tienilic acid were higher compared to the reactivities of their conjugated metabolites, with NADPH-dependent covalent binding of 250 pmol drug eq/mg protein for both drugs. The seven drugs all formed UDPGA-dependent acyl glucuronides, but none of these resulted in covalent binding. This study shows that, unlike studies with hepatocytes or in vivo, human liver microsomes provide an opportunity to investigate the reactivity of individual metabolites.

Chemical Research in Toxicology published new progress about Drug toxicity. 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

Chen, Minjun published the artcileA Model to predict severity of drug-induced liver injury in humans, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is human drug liver injury.

Drug-induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule-of-2 (RO2) and found lipophilicity (logP ≥3) and daily dose ≥100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quant. metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration-approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quant. assessment of risk of clin. DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chem. structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clin. cases collected from the National Institutes of Health’s LiverTox database to demonstrate that the DILI score correlated with the severity of clin. outcome. Conclusions: Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (Hepatol. 2016;64:931-940).

Hepatology (Hoboken, NJ, United States) published new progress about Drug toxicity. 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

Melet, Armelle published the artcileSubstrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is substrate recognition cytochrome P450 2C9 diclofenac sulfaphenazole tienilic acid.

A series of six site-directed mutants of CYP 2C9 were constructed with the aim to better define the amino acid residues that play a critical role in substrate selectivity of CYP 2C9, particularly in three distinctive properties of this enzyme: (i) its selective mechanism-based inactivation by tienilic acid (TA), (ii) its high affinity and hydroxylation regioselectivity toward diclofenac, and (iii) its high affinity for the competitive inhibitor sulfaphenazole (SPA). The S365A mutant exhibited kinetic characteristics for the 5-hydroxylation of TA very similar to those of CYP 2C9; however, this mutant did not undergo any detectable mechanism-based inactivation by TA, which indicates that the OH group of Ser 365 could be the nucleophile forming a covalent bond with an electrophilic metabolite of TA in TA-dependent inactivation of CYP 2C9. The F114I mutant was inactive toward the hydroxylation of diclofenac; moreover, detailed analyses of its interaction with a series of SPA derivatives by difference visible spectroscopy showed that the high affinity of SPA to CYP 2C9 (Ks=0.4 μM) was completely lost when the Ph substituent of Phe 114 was replaced with the alkyl group of Ile (Ks=190±20 μM), or when the Ph substituent of SPA was replaced with a cyclohexyl group (Ks=120±30 μM). However, this cyclohexyl derivative of SPA interacted well with the F114I mutant (Ks=1.6±0.5 μM). At the opposite end, the F94L and F110I mutants showed properties very similar to those of CYP 2C9 toward TA and diclofenac. Finally, the F476I mutant exhibited at least three main differences compared to CYP 2C9: (i) big changes in the kcat and Km values for TA and diclofenac hydroxylation, (ii) a 37-fold increase of the Ki value found for the inhibition of CYP 2C9 by SPA, and (iii) a great change in the regioselectivity of diclofenac hydroxylation, the 5-hydroxylation of this substrate by CYP 2C9 F476I exhibiting a kcat of 28 min-1. These data indicate that Phe 114 plays an important role in recognition of aromatic substrates of CYP 2C9, presumably via Π-stacking interactions. They also provide the first exptl. evidence showing that Phe 476 plays a crucial role in substrate recognition and hydroxylation by CYP 2C9.

Archives of Biochemistry and Biophysics published new progress about Covalent bond. 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

Obach, R. Scott published the artcileCan In Vitro Metabolism-Dependent Covalent Binding Data in Liver Microsomes Distinguish Hepatotoxic from Nonhepatotoxic Drugs? An Analysis of 18 Drugs with Consideration of Intrinsic Clearance and Daily Dose, COA of Formula: C13H8Cl2O4S, the main research area is drug hepatotoxicity screening metabolism covalent binding liver.

In vitro covalent binding assessments of drugs have been useful in providing retrospective insights into the association between drug metabolism and a resulting toxicol. response. On the basis of these studies, it has been advocated that in vitro covalent binding to liver microsomal proteins in the presence and the absence of NADPH be used routinely to screen drug candidates. However, the utility of this approach in predicting toxicities of drug candidates accurately remains an unanswered question. Importantly, the years of research that have been invested in understanding metabolic bioactivation and covalent binding and its potential role in toxicity have focused only on those compounds that demonstrate toxicity. Investigations have not frequently queried whether in vitro covalent binding could be observed with drugs with good safety records. Eighteen drugs (nine hepatotoxins and nine nonhepatotoxins in humans) were assessed for in vitro covalent binding in NADPH-supplemented human liver microsomes. Of the two sets of nine drugs, seven in each set were shown to undergo some degree of covalent binding. Among hepatotoxic drugs, acetaminophen, carbamazepine, diclofenac, indomethacin, nefazodone, sudoxicam, and tienilic acid demonstrated covalent binding, while benoxaprofen and felbamate did not. Of the nonhepatotoxic drugs evaluated, buspirone, diphenhydramine, meloxicam, paroxetine, propranolol, raloxifene, and simvastatin demonstrated covalent binding, while ibuprofen and theophylline did not. A quant. comparison of covalent binding in vitro intrinsic clearance did not sep. the two groups of compounds, and in fact, paroxetine, a nonhepatotoxin, showed the greatest amount of covalent binding in microsomes. Including factors such as the fraction of total metabolism comprised by covalent binding and the total daily dose of each drug improved the discrimination between hepatotoxic and nontoxic drugs based on in vitro covalent binding data; however, the approach still would falsely identify some agents as potentially hepatotoxic.

Chemical Research in Toxicology published new progress about Covalent bond. 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

Gross, Aaron D. published the artcileToxicity and synergistic activities of chalcones against Aedes aegypti (Diptera: Culicidae) and Drosophila melanogaster (Diptera: Drosophilidae), Quality Control of 40180-04-9, the main research area is Aedes Drosophila chalcone synergist insecticide; insecticide; larvicide; mosquito; synergist.

Mosquito-borne illnesses are of great concern throughout the world, and chem. insecticides are commonly employed to decrease mosquito populations. However, the developmental insecticide pipeline for vector control has primarily been filled by repurposed agricultural products, and is hampered by their widespread use and insecticide resistance. The present study was performed in the search for new chem. insecticides or insecticide synergists. Screening of 31 chalcone analogs was performed using Aedes aegypti (Linnaeus) first-instar larval toxicity assay, and oral feeding to Drosophila melanogaster’s proper authority should be (Meigen). Synergism studies were performed by topically applying chalcones to adult female Ae. aegypti mosquitoes to examine its impact on activity of carbaryl, which was compared to piperonyl butoxide alone. Fourteen chalcone analogs had LC50 values in the range of 0.4-38ppm against first-instar Ae. aegypti larvae, and three chalcones displayed toxicity against D. melanogaster via feeding (LC50 values ranged from 146-214μg/mL). Two chalcones synergized carbaryl toxicity against adult Ae. aegypti with efficacy similar to piperonyl butoxide. As a result, it is concluded that chalcones may serve as novel insecticides and synergists after further structural optimization.

Journal of Medical Entomology published new progress about Aedes aegypti. 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

Abrams, Roman published the artcilePhotocatalytic Difunctionalization of Vinyl Ureas by Radical Addition Polar Truce-Smiles Rearrangement Cascades, COA of Formula: C6H6OS, the main research area is vinyl urea difunctionalization photocatalyst radical polar Truce Smiles rearrangement; SNAr; photochemistry; rearrangement; trifluoromethylation; urea.

The authors report tandem alkyl-arylations and phosphonyl-arylations of vinyl ureas by way of a photocatalytic radical-polar crossover mechanism. Addition of photoredox-generated radicals to the alkene forms a new C-C or C-P bond and generates a product radical adjacent to the urea function. Reductive termination of the photocatalytic cycle generates an anion that undergoes a polar Truce-Smiles rearrangement, forming a C-C bond. The reaction is successful with a range of α-fluorinated alkyl sodium sulfinate salts and diarylphosphine oxides as radical precursors, and the conformationally accelerated Truce-Smiles rearrangement is not restricted by the electronic nature of the migrating aromatic ring. Formally the reaction constitutes an α,β-difuctionalization of a carbon-carbon double bond, and proceeds under mild conditions with visible light and a readily available organic photocatalyst. The products are α,α-diaryl alkylureas typically functionalized with F or P substituents that may be readily converted into α,α-diaryl alkylamines.

Angewandte Chemie, International Edition published new progress about Photocatalysts. 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

Meyer, Michael D. published the artcileStructure-Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α1A Adrenoceptor Antagonists as Potential Agents for the Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH), Computed Properties of 67189-92-8, the main research area is alpha1A adrenoceptor uroselective hexahydrobenzisoindole synthesis.

In search of a uroselective agent that exhibits a high level of selectivity for the α1A receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochem. of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the α1 adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.

Journal of Medicinal Chemistry published new progress about Pharmacophores. 67189-92-8 belongs to class benzothiophene, name is Ethyl 3-amino-4-chlorobenzo[b]thiophene-2-carboxylate, and the molecular formula is C11H10ClNO2S, Computed Properties of 67189-92-8.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Usui, Toru published the artcileEvaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins, Computed Properties of 40180-04-9, the main research area is drug toxicity liver protein binding.

Prediction of idiosyncratic drug-induced liver injury (DILI) is difficult, and the underlying mechanisms are not fully understood. However, many drugs causing DILI are considered to form reactive metabolites and covalently bind to cellular macromols. in the liver. The objective of this study was to clarify whether the risk of idiosyncratic DILI can be estimated by comparing in vitro covalent binding (CB) levels among 12 pos. compounds (acetaminophen, alpidem, bromfenac, carbamazepine, diclofenac, flutamide, imipramine, nefazodone, tacrine, ticlopidine, tienilic acid, and troglitazone) for DILI and 12 neg. compounds (acetylsalicylic acid, caffeine, dexamethasone, losartan, ibuprofen, paroxetine, pioglitazone, rosiglitazone, sertraline, theophylline, venlafaxine, and zolpidem). After incubation with human liver microsomes in the presence of NADPH, there was a large overlap in the distribution of CB amounts between the pos. and neg. groups. On addition of UDP-glucuronic acid (UDPGA) as a cofactor for glucuronidation, the CB levels of bromfenac and diclofenac were increased. With addition of nucleophilic glutathione (GSH), values for most compounds were decreased. However, separation of the two groups on the basis of CB could not be improved by UDPGA or GSH. Furthermore, CB with human hepatocytes also failed to discriminate pos. from neg. compounds Therefore, the CB amount alone is not sufficient for risk assessment of DILI. In contrast, when the CB amount was multiplied by the maximum daily dose, which may reflect maximum hepatic exposure, the two groups did become discriminated. Taken together, our findings suggest that the combination of CB amount and daily dose can estimate the risk of idiosyncratic DILI.

Drug Metabolism and Disposition published new progress about Hepatotoxicity. 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

Saito, Junichiro published the artcileHigh content analysis assay for prediction of human hepatotoxicity in HepaRG and HepG2 cells, Formula: C13H8Cl2O4S, the main research area is drug induced liver injury human hepatocyte cytochrome P450 glutathione; GSH; HCA; HepG2; HepaRG; Hepatotoxicity; ROS.

Drug-induced liver injury (DILI) results in the termination of drug development or withdrawal of a drug from the market. The establishment of a predictive, high-throughput preclin. test system to evaluate potential clin. DILI is therefore required. Here, the authors established a high content anal. (HCA) assay in human hepatocyte cell lines such as the HepaRG with normal expression levels of CYP enzymes and HepG2 with extremely low expression levels of CYP enzymes. Clin. DILI or non-DILI compounds were evaluated for reactive oxygen species (ROS) production, glutathione (GSH) consumption, and mitochondrial membrane potential (MMP) attenuation. A proportion of DILI compounds induced ROS generation, GSH depletion, and MMP dysfunction, which was consistent with reported mechanisms of DILI of these compounds In particular, DILI compounds that deplete GSH via reactive metabolites exhibited a more marked decrease in intracellular GSH or increase in ROS production in HepaRG cells than in HepG2 cells. Comparison of the two cell lines with different levels of CYP expression might help clarify the contribution of metabolism to hepatocyte toxicity. These results suggest that the HCA assay in HepaRG and HepG2 cells might help improve the accuracy of evaluating clin. DILI potential during drug screening.

Toxicology In Vitro published new progress about Hepatotoxicity. 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

Rincon-Villamizar, Edgar published the artcileRules relating hepatotoxicity with structural attributes of drugs, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is hepatotoxicity drug mol structure.

The relationship between mol. structures of drugs and their hepatotoxicity was studied by characterizing their structure in a new way and using formal concept anal., a math. technique to condense knowledge into particular rules, which does not imply linearly assumptions as many conventional statistical techniques. The structural characterization was based on mol. descriptors and mol. frameworks, further decomposed into structural elements, rings, and bridges. The methodol. was applied to drugs in the liver toxicity knowledge base database with the potential to cause drug-induced liver injury. Numbers of atoms and bonds along with the aromatic ratio were suitable descriptors for such drugs. The higher the number of rings and asym. structural elements in their terminal ring systems, the higher is the probability of hepatotoxicity. Rules were found which may help to design drugs which are unlikely to be hepatotoxic.

Toxicological & Environmental Chemistry published new progress about Drugs of abuse. 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