Category: 40180-04-9

Surapaneni, Sekhar published the artcileAbsorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is ozanimod sphingosine phosphate receptor modulator absorption metabolism excretion pharmacol.

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, resp. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alc. dehydrogenase, cytochrome P 450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3β- and 11β-hydroxysteroid dehydrogenase, and this reversible oxidoredn. between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development.

Drug Metabolism & Disposition published new progress about Absorption. 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

Lopez-Garcia, M. Pilar published the artcileThiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: Inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is thiophene derivative cytochrome P4502C9 suicide substrate; tienilate metabolite cytochrome P4502C9 suicide substrate; immunoallergic hepatitis tienilate metabolite cytochrome P4502C9.

Oxidation of tienilic acid (TA) by microsomes of yeast expressing two closely related human liver cytochrome P-450s (P 450), P 450 2C9 and 2C10, led to catalysis-dependent loss of activity of these P450s. Under identical conditions, oxidation of a tienilic acid isomer (TAI) failed to give any P 450 inactivation. The loss of P 450 activity during TA oxidation was concomitant with product (5-hydroxytienilic acid, 5-OHTA) formulation, showed pseudo-first-order and saturation kinetics, and was inhibited by an alternative substrate, tolbutamide. Covalent binding of TA metabolites to microsomal proteins occurred in parallel with enzyme inactivation and was partially inhibited by the presence of glutathione in the reaction medium. However, glutathione did not protect P 450 enzyme from inactivation. Thus, TA exhibited all of the characteristics of a mechanism-based inactivator for P 450 2C9 and 2C10 enzymes. The following kinetic parameters were determined in the case of P 450 2C10: t1/2,max = 3.4 min, kinact = 3.6 10-3 s-1, KI = 4.3 μM, kinact/K1 = 813 L mol-1 s-1, and partition ratio = 11.6. Moreover, a specific covalent binding of 0.9 mol of TA metabolite per mol of P 450 2C10 was found to occur before the complete loss of enzyme activity (in incubations performed in the presence of glutathione). A plausible mechanism for P 450 2C10 (2C9) inactivation during TA oxidation is proposed. It involves the intermediate formation of an electrophilic thiophene sulfoxide, which may react at position 5 of its thiophene ring either with H2O to give 5-OHTA or with a nucleophilic group of an amino acid residue of the P 450 active site, which results in its covalent binding to P 450 protein. This alkylation and inactivation of P 450 2C9 (2C10) by TA could be a starting point for the appearance of anti-P 4502C antibodies detected in patients treated with TA and suffering from immunoallergic hepatitis.

Biochemistry published new progress about Alkylation. 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

Chan, Alix I. published the artcileDiscovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is human kinase MAP2K6 inhibitor DNA encoded small mol library.

We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small mols. and unpurified protein targets in cell lysates. In this study we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding partners out of 32,096 possible combinations in a single solution-phase library × library experiment The results recapitulated known small mol.:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase. Ethacrynic acid inhibits MAP2K6 in part through alkylation of a non-conserved cysteine residue. This work validates the ability of IDUP to discover ligands for proteins of biomedical relevance.

Journal of the American Chemical Society published new progress about Alkylation. 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 of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Sangion, Alessandro published the artcilePBT assessment and prioritization of contaminants of emerging concern: Pharmaceuticals, Application In Synthesis of 40180-04-9, the main research area is persistence bioaccumulation toxicity assessment prioritization contaminant emerging concern pharmaceutical; PBT; Pharmaceuticals; Prioritization; QSAR; Screening.

The strong and widespread use of pharmaceuticals, together with incorrect disposal procedures, has recently made these products contaminants of emerging concern (CEC). Unfortunately, little is known about pharmaceuticals’ environmental behavior and ecotoxicity, so that EMEA (European Medicines Agency) released guidelines for the pharmaceuticals’ environmental risk assessment. In particular, there is a severe lack of information about persistence, bioaccumulation and toxicity (PBT) of the majority of the thousands of substances on the market. Computational tools, like QSAR (Quant. Structure Activity Relationship) models, are the only way to screen large sets of chems. in short time, with the aim of ranking, highlighting and prioritizing the most environmentally hazardous for focusing further exptl. studies. In this work we propose a screening method to assess the potential persistence, bioaccumulation and toxicity of more than 1200 pharmaceutical ingredients, based on the application of two different QSAR models. We applied the Insubria-PBT Index, a MLR (Multiple Linear Regression) QSAR model based on four simple mol. descriptors, implemented in QSARINS software, and able to synthesize the PBT potential in a unique cumulative value and the US-EPA PBT Profiler that assesses the PBT behavior evaluating sep. P, B and T. Particular attention was given to the study of Applicability Domain in order to provide reliable predictions. An agreement of 86% was found between the two models and a priority list of 35 pharmaceuticals, highlighted as potential PBTs by consensus, was proposed for further exptl. validation. Moreover, the results of this computational screening are in agreement with preliminary exptl. data in the literature. This study shows how in silico models can be applied in the hazard assessment to perform preliminary screening and prioritization of chems., and how the identification of the structural features, mainly associated with the potential PBT behavior of the prioritized pharmaceuticals, is particularly relevant to perform the rational a priori design of new, environmentally safer, pharmaceuticals.

Environmental Research published new progress about Analgesics. 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

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

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

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

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

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

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