Day: November 17, 2022

Gramec, Darja published the artcileBioactivation Potential of Thiophene-Containing Drugs, SDS of cas: 40180-04-9, the main research area is review thiophene derivative metabolism hepatotoxicity.

Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P 450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound’s toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples.

Chemical Research in Toxicology published new progress about Drug metabolism. 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, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Uetrecht, Jack published the artcileRole of drug metabolism for breaking tolerance and the localization of drug hypersensitivity, Application In Synthesis of 40180-04-9, the main research area is review drug reactive metabolite tolerance hypersensitivity penicillamine nevirapine modeling.

There are 3 major working hypotheses for the mechanism of drug hypersensitivity reactions: the hapten hypotheses, the danger hypothesis and the PI hypothesis. These hypotheses are difficult to test because of the idiosyncratic nature of hypersensitivity reactions. There is evidence that reactive metabolites are involved in many hypersensitivity reactions, and the reactive metabolite is often formed in the target organ of toxicity, presumably because the half-life of most reactive metabolites is too short to allow them to reach distant sites. In the case of less reactive species that freely circulate the pattern of hypersensitivity usually fits that expected of an extracellular antigen, specifically, an antibody-mediated reaction. The authors have used 2 animal models: penicillamine-induced autoimmunity and nevirapine-induced skin rash in Brown Norway rats to test hypotheses. The authors have found that tolerance is readily induced with a lower dose of the drug, although the nature of tolerance is different in the 2 models. In the penicillamine model, tolerance is immune-mediated and can be overcome by agents that act as a danger signal. Reactive metabolites may also act as a danger signal. The models can also be used to test the role of reactive species in the mechanism of hypersensitivity reactions.

Toxicology published new progress about Drug metabolism. 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

Preusch, Peter C. published the artcileVitamin K1 2,3-epoxide and quinone reduction: mechanism and inhibition, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is vitamin K1 epoxide quinone reduction microsome; reductase vitamin K epoxide microsome; DT diaphorase vitamin K metabolism microsome.

The chem. and enzymic pathways of vitamin K1 epoxide and quinone reduction have been investigated. Na borohydride treatment resulted in carbonyl reduction generating relatively stable compounds that did not proceed to quinone in the presence of base. NAD(P)H:quinone oxidoreductase (DT-diaphorase) reduction of vitamin K to the hydroquinone was a significant process in intact microsomes, but 1/5th the rate of the dithiothreitol (DTT)-dependent reduction No evidence was found for DT-diaphorase catalyzed reduction of vitamin K1 epoxide, nor was it capable of mediating transfer of electrons from NADH to the microsomal epoxide reducing enzyme. Purified diaphorase reduced detergent-solubilized vitamin K1 10-5 as rapidly as it reduced dichlorophenylindophenol (DCPIP). Reduction of 10 μM vitamin K1 by 200 μM NADH was not inhibited by 10 μM dicoumarol, whereas DCPIP reduction was fully inhibited. In contrast to vitamin K3 (menadione), vitamin K1 (phylloquinone) did not stimulate microsomal NADPH consumption in the presence or absence of dicoumarol. DTT-dependent vitamin K epoxide reduction and vitamin K reduction were shown to be mutually inhibitory reactions, suggesting that both occur at the same enzymic site. On this basis, a mechanism for reduction of the quinone by thiols is proposed. Both the DTT-dependent reduction of vitamin K1 epoxide and quinone, and the reduction of DCPIP by purified DT-diaphorase were inhibited by dicoumarol, warfarin, lapachol, and sulfaquinoxaline.

Free Radical Research Communications published new progress about Disulfide group. 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

Rattie, Elisabeth S. published the artcileA dissolution anomaly involving ticrynafen in simulated intestinal fluid without enzyme, HPLC of Formula: 40180-04-9, the main research area is ticrynafen dissolution intestinal fluid; potassium ticrynafen dissolution.

Data are presented showing that the anomalous dissolution behavior of ticrynafen (I) [40180-04-9] in simulated intestinal fluid without enzyme is due to the presence of K+ in the dissolution medium. Solubility studies indicate that an insoluble 1:1 complex is formed between I and I K salt [81943-63-7]. This complex apparently creates an insoluble barrier that prevents complete dissolution of I. To determine whether this might also occur in clin. use, a 3-way cross-over study in 12 subjects was done. Concomitant administration of I tablets and K in the form of a com. supplement does not adversely affect bioavailability.

Journal of Pharmaceutical Sciences published new progress about Digestive tract. 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

Li, Weina published the artcileVisible-Light-Promoted Carbene Insertion and Decarbonylation for the Synthesis of α-Substituted γ-Ketoesters, Product Details of C6H6OS, the main research area is ketoester green preparation; enaminone diazoester carbene insertion decarbonylation visible light promoted.

Herein, a blue visible-light-promoted approach to prepare a variety of α-substituted γ-ketoesters derivatives RC(O)CH2C(COOR1)R2R3 [R = Ph, 3-FC6H4, 4-MeC6H4, etc.; R1 = Me, Et; R2 = H, CHO; R3 = Ph, 4-ClC6H4, 3-thienyl, etc.] through carbene insertion and the decarbonylation of enaminones and diazoesters was reported. These reactions used readily available starting materials, as well as transition-metal-free, eco-friendly procedures that were amenable to gram-scale synthesis and wide functional group tolerance. This methodol. might be useful for constructing polysubstituted heterocycles with potential biol. activity.

Journal of Organic Chemistry published new progress about Decarbonylation. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Product Details of C6H6OS.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Contrera, Joseph F. published the artcileEstimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose, Computed Properties of 40180-04-9, the main research area is QSAR structure activity relationship mol modeling drug screening.

Estimating the maximum recommended starting dose (MRSD) of a pharmaceutical for phase I human clin. trials and the no observed effect level (NOEL) for non-pharmaceuticals is currently based exclusively on an extrapolation of the results of animal toxicity studies. This process is inexact and requires the results of toxicity studies in multiple species (rat, dog, and monkey) to identify the no observed adverse effect level (NOAEL) and most sensitive test species. Multiple uncertainty (safety) factors are also necessary to compensate for incompatibility and uncertainty underlying the extrapolation of animal toxicity to humans. The maximum recommended daily dose for pharmaceuticals (MRDD) is empirically derived from human clin. trials. The MRDD is an estimated upper dose limit beyond which a drug’s efficacy is not increased and/or undesirable adverse effects begin to outweigh beneficial effects. The MRDD is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicol.) or undesirable pharmacol. effects are observed The NOAEL in test animals is currently used to estimate the safe starting dose in human clin. trials. MDL QSAR predictive modeling of the human MRDD may provide a better, simpler and more relevant estimation of the MRSD for pharmaceuticals and the toxic dose threshold of chems. in humans than current animal extrapolation based risk assessment models and may be a useful addition to current methods. A database of the MRDD for over 1300 pharmaceuticals was compiled and modeled using MDL QSAR software and E-state and connectivity topol. descriptors. MDL QSAR MRDD models were found to have good predictive performance with 74-78% of predicted MRDD values for 120 internal and 160 external validation compounds falling within a range of ±10-fold the actual MRDD value. The predicted MRDD can be used to estimate the MRSD for pharmaceuticals in phase I clin. trials with the addition of a 10-fold safety factor. For non-pharmaceutical chems. any compound-related effect can be considered an undesirable and adverse toxicol. effect and the predicted MRDD can be used to estimate the NOEL with the addition of an appropriate safety factor.

Regulatory Toxicology and Pharmacology published new progress about Clinical trials. 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

Jaladanki, Chaitanya K. published the artcileToxicity Originating from Thiophene Containing Drugs: Exploring the Mechanism using Quantum Chemical Methods, Application In Synthesis of 40180-04-9, the main research area is thiophene drug toxicity quantum chem cytochrome P 450 metabolism.

Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S-oxidation and epoxidation In this work, the mol. level details of the bioinorganic chem. associated with the generation of these competitive reactions are reported. D. functional theory was utilized (i) to explore the mol. mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH- as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the at. level.

Chemical Research in Toxicology published new progress about Aplastic anemia. 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

Martin, Parthena published the artcileIn vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions, Product Details of C13H8Cl2O4S, the main research area is liver cell fenfluramine norfenfluramine drug interaction; antiepileptics; cytochrome P450; drug transport; drug-drug interactions.

Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood-onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To assess risk of drug interaction affecting pharmacokinetics of FFA and its major metabolite, norfenfluramine (nFFA), we conducted in vitro metabolite characterization, reaction phenotyping, and drug transporter-mediated cellular uptake studies. FFA showed low in vitro clearance in human liver S9 fractions and in intestinal S9 fractions in all three species tested (t1/2 > 120 min). Two metabolites (nFFA and an N-oxide or a hydroxylamine) were detected in human liver microsomes vs. six in dog and seven in rat liver microsomes; no metabolite was unique to humans. Selective CYP inhibitor studies showed FFA metabolism partially inhibited by quinidine (CYP2D6, 48%), phencyclidine (CYP2B6, 42%), and furafylline (CYP1A2, 32%) and, to a lesser extent (<15%), by tienilic acid (CYP2C9), esomeprazole (CYP2C19), and troleandomycin (CYP3A4/5). Incubation of nFFA with rCYP1A2, rCYP2B6, rCYP2C19, and rCYP2D6 resulted in 10%-20% metabolism and no clear inhibition of nFFA metabolism by any CYP-selective inhibitor. Reaction phenotyping showed metabolism of FFA by recombinant human cytochrome P 450 (rCYP) enzymes rCYP2B6 (10%-21% disappearance for 1 and 10μM FFA, resp.), rCYP1A2 (22%-23%), rCYP2C19 (49%-50%), and rCYP2D6 (59%-97%). Neither FFA nor nFFA was a drug transporter substrate. Results show FFA metabolism to nFFA occurs through multiple pathways of elimination. FFA dose adjustments may be needed when administered with strong inhibitors or inducers of multiple enzymes involved in FFA metabolism (e.g., stiripentol). Pharmacology Research & Perspectives published new progress about Anticonvulsants. 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

Pogrebnoi, A. A. published the artcileModeling complexes of substrates with cytochrome P450 2C9, Category: benzothiophene, the main research area is modeling substrate cytochrome P450 2C9 algorithm CiS complex.

Complexes of 16 substrates with 2C9 isoform of Cytochrome P 450 complex taken from the PDB database have been modeled using 3D-QSAR algorithm CiS. The arrangement of substrate mols. and the orientation of their reaction centers with respect to the heme in modeled complexes have been analyzed. The orientation of substrate mols. in the model complexes explains the exptl. observed metabolic reactions. The results show that the CiS algorithm is capable of predicting the metabolic pathways of the modeled complexes.

Pharmaceutical Chemistry Journal published new progress about Algorithm (CiS). 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

Nakayama, Shintaro published the artcileA zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is idiosyncratic drug toxicity daily dose covalent binding risk assessment.

The risk of idiosyncratic drug toxicity (IDT) is of great concern to the pharmaceutical industry. Current hypotheses based on retrospective studies suggest that the occurrence of IDT is related to covalent binding and daily dose. The authors determined the covalent binding of 42 radiolabeled drugs in three test systems (human liver microsomes and hepatocytes in vitro and rat liver in vivo) to assess the risk of IDT. On the basis of safety profiles given in official documentation, tested drugs were classified into the safety categories of safe, warning, black box warning, and withdrawn. The covalent binding in each of the three test systems did not distinguish the safety categories clearly. However, when the log-normalized covalent binding was plotted against the log-normalized daily dose, the distribution of the plot in the safety categories became clear. An ordinal logistic regression anal. indicated that both covalent binding and daily dose were significantly correlated with safety category and that covalent binding in hepatocytes was the best predictor among the three systems. When two separation lines were drawn on the correlation graph between covalent binding in human hepatocytes and daily dose by a regression anal. to create three zones, 30 of 37 tested drugs were located in zones corresponding to their resp. classified safety categories. In conclusion, the authors established a zone classification system using covalent binding in human hepatocytes and daily dose for the risk assessment of IDTs.

Drug Metabolism and Disposition published new progress about Agranulocytosis. 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