Category: 40180-04-9

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 Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis.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

Masubuchi, Noriko published the artcilePrediction of in Vivo Potential for Metabolic Activation of Drugs into Chemically Reactive Intermediate: Correlation of in Vitro and in Vivo Generation of Reactive Intermediates and in Vitro Glutathione Conjugate Formation in Rats and Humans, Formula: C13H8Cl2O4S, the main research area is drug metabolic activation glutathione conjugate formation toxicity.

The covalent binding of reactive intermediates to macromols. might have potential involvement in severe adverse drug reactions. Thus, quantification of reactive metabolites is necessary during the early stage of drug discovery to avoid serious toxicity. In this study, the relation between covalent binding and glutathione (GSH) conjugate formation in rat and human liver microsomes were investigated using 10 representative radioactive compounds that have been reported as hepatotoxic or having other toxicity derived from their reactive intermediates: acetaminophen, amodiaquine, carbamazepine, clozapine, diclofenac, furosemide, imipramine, indomethacin, isoniazid, and tienilic acid, all at a concentration of 10 μM. The GSH conjugate formation rate correlates well with the covalent binding of radioactivity (both rat and human, r2 = 0.93), which suggests that quantification of the GSH conjugate can be used to estimate covalent binding. To quantify the GSH-conjugation rate with non-radiolabeled compounds in vitro, the validation study for the determination of GSH conjugate formation using 35S-GSH by radio-HPLC was useful to predict metabolic activation. Following oral administration of 20 mg/kg of the radiolabeled compounds to rats, radioactivity that covalently bound to plasma and liver proteins was determined The in vivo maximum covalent binding level in liver based on the free fraction of plasma area under the concentration curve (AUC) and in vitro covalent binding rate was found to correlate well (r2 = 0.79). Therefore, this model for in vitro covalent binding studies in human and rat and in vivo rat studies might be useful in predicting human metabolic activation of compounds

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, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Yu, Ke published the artcileHigh daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury, HPLC of Formula: 40180-04-9, the main research area is drug induced liver injury cytochrome P450.

Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P 450 (P 450) enzymes are primarily involved in hepatic metabolism Identifying the associations of DILI with drugs that are P 450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P 450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations We revealed that drugs that are substrates of P 450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P 450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P 450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65-3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clin. settings. Drug Metabolism & Disposition 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Tay, Suzanne published the artcileMechanistic studies of the cationic binding pocket of CYP2C9 in vitro and in silico: metabolism of nonionizable analogs of tienilic acid, HPLC of Formula: 40180-04-9, the main research area is CYP2C9 tienilic acid metabolism liver microsome.

Tienilic acid (TA) is selectively oxidized at the C-5 position of the thiophene ring by the human liver enzyme cytochrome P 450 2C9 (CYP2C9). This oxidation is mediated by the proximal positioning of the thiophene over the heme iron, which is proposed to be coordinated by an interaction of the TA carboxylic acid to a cationic binding pocket in the enzyme active site. In this study, we investigated how chem. modification of TA influences the bioactivation by CYP2C9. For this investigation, nine analogs of TA were chosen with substitutions on either side of the mol. We tested three parameters, including CYP2C9 inhibition, metabolic profiling, and in silico docking. Of the 10 compounds tested, only two (TA and a noncarboxyl analog) resulted in competitive and time-dependent inhibition of CYP2C9. Metabolic profiling revealed a trend in which substitution of the carboxylate with nonionizable functional groups resulted in metabolic switching from oxidation of the aromatic ring to dealkylation reactions at the opposite side of the structure. The in silico modeling predicted an opposite binding orientation to that of TA for many analogs, including the 3-thenoyl regio-isomer analog, which contradicts previous models. Together these data show that disrupting interactions with the cationic binding pocket of CYP2C9 will impact the sites of metabolism and inhibition of the enzyme.

Drug Metabolism & Disposition 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Berry, Loren M. published the artcileDynamic modeling of cytochrome P450 inhibition in vitro: impact of inhibitor depletion on IC50 shift, HPLC of Formula: 40180-04-9, the main research area is CYP3A4 CYP2C9 CYP2D6 protein inhibitor liver microsome clarithromycin dasatinib.

The impact of inhibitor depletion on the determination of shifted IC50 (IC50 determined after 30 min of preincubation with inhibitor) is examined In addition, IC50-shift data are analyzed using a mechanistic model that incorporates the processes of inhibitor depletion, as well as reversible and time-dependent inhibition. Anomalies such as a smaller-than-expected shift in IC50 and even increases in IC50 with preincubation were explained by the depletion of inhibitor during the preincubation. The IC50-shift assay remains a viable approach to characterizing a wide range of reversible and time-dependent inhibitors. However, as with more traditional time-dependent inactivation methods, it is recommended that IC50-shift exptl. data be interpreted with some knowledge of the magnitude of inhibitor depletion. For the most realistic classification of time-dependent inhibitors using IC50-shift methods, shifted IC50 should be calculated using observed inhibitor concentrations at the end of the incubation rather than nominal inhibitor concentrations Finally, a mechanistic model that includes key processes, such as competitive inhibition, enzyme inactivation, and inhibitor depletion, can be used to describe accurately the observed IC50 and shifted IC50 curves. For compounds showing an IC50 fold shift >1.5 based on the observed inhibitor concentrations, reanalyzing the IC50-shift data using the mechanistic model appeared to allow for reasonable estimation of KI, KI, and kinact directly from the IC50 shift experiments

Drug Metabolism & Disposition 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Sheridan, Robert P. published the artcileEmpirical Regioselectivity Models for Human Cytochromes P450 3A4, 2D6, and 2C9, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is QSAR regioselectivity model cytochrome P450 isoform drug metabolism.

Cytochromes P 450 3A4, 2D6, and 2C9 metabolize a large fraction of drugs. Knowing where these enzymes will preferentially oxidize a mol., the regioselectivity, allows medicinal chemists to plan how best to block its metabolism The authors present QSAR-based regioselectivity models for these enzymes calibrated against compiled literature data of drugs and drug-like compounds These models are purely empirical and use only the structures of the substrates, in contrast to those models that simulate a specific mechanism like hydrogen radical abstraction, and/or use explicit models of active sites. The authors most predictive models use three substructure descriptors and two phys. property descriptors. Descriptor importance from the random forest QSAR method show that other factors than the immediate chem. environment and the accessibility of the hydrogen affect regioselectivity in all three isoforms. The cross-validated predictions of the models are compared to predictions from the authors earlier mechanistic model (Singh et al. J. Med. Chem. 2003, 46, 1330-1336) and predictions from MetaSite (Cruciani et al. J. Med. Chem. 2005, 48, 6970-6979).

Journal of Medicinal Chemistry 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Kingsley, Laura J. published the artcileCombining Structure- and Ligand-Based Approaches to Improve Site of Metabolism Prediction in CYP2C9 Substrates, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome p450 substrate metabolism site prediction QSAR simulation.

Purpose: Predicting atoms in a potential drug compound that are susceptible to oxidation by cytochrome P 450 (CYP) enzymes is of great interest to the pharmaceutical community. We aimed to develop a computational approach combining ligand- and structure-based design principles to accurately predict sites of metabolism (SoMs) in a series of CYP2C9 substrates. Methods: We employed the reactivity model, SMARTCyp, ensemble docking, and pseudo-receptor modeling based on quant. structure-activity relationships (QSAR) to account for influences of both the inherent reactivity of each atom and the phys. structure of the CYP2C9 binding site. Results: We tested ligand-based prediction alone (i.e. SMARTCyp), structure-based prediction alone (i.e. AutoDock Vina docking), the linear combination of the SMARTCYP and docking scores, and finally a pseudo-receptor QSAR model based on the docked compounds in combination with SMARTCyp. We found that by using the latter combined approach we were able to accurately predict 88% and 96% of the true SoMs, within the top-1 and top-2 predictions, resp. Conclusions: We have outlined a novel combination approach for accurately predicting SoMs in CYP2C9 ligands. We believe that this method may be applied to other CYP2C9 ligands as well as to other CYP systems.

Pharmaceutical Research 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Neau, E. published the artcileHydroxylation of the thiophene ring by hepatic monooxygenases. Evidence for 5-hydroxylation of 2-aroylthiophenes as a general metabolic pathway using a simple UV-visible assay, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilic acid hydroxylation liver monooxygenase; thiophene aryl hydroxylation liver monooxygenase.

The 5-hydroxylation of tienilic acid (I) by rat liver microsomes was measured by a new, simple method involving the detection of 5-hydroxytienilic acid (II) by UV-visible spectroscopy. This assay allowed continuous detection of this metabolite and was easily used to determine the kinetic parameters of the reaction (Vmax and Km being resp., 1 nmol product formed/mg protein/min and 14 μM for liver microsomes from phenobarbital-treated rats). This activity was dependent on NADPH and inhibited by CO, SKF 525A and metyrapone, indicating that it is dependent on cytochromes P 450. The UV-visible assay is based on intrinsic properties of 5-hydroxy-2-aroylthiophenes which exist as highly conjugated anions at physiol. pH and exhibit large ε values around 390 nm. Its application to other 2-aroylthiophenes like suprofen, 2-p-chlorobenzoylthiophene and a series of 2-aroylthiophenes with various substituents on the aroyl group showed that, in general, thiophene compounds bearing a 2-arylketo substituent appear to be hydroxylated at position 5 by rat liver microsomes. The kinetic parameters of the 5-hydroxylation of suprofen and 2-p-chlorobenzoylthiophene by liver microsomes from phenobarbital-treated rats were determined and found to be similar to those for I hydroxylation.

Biochemical Pharmacology published new progress about Enzyme kinetics. 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

Jean, Pascale published the artcileOxidation of tienilic acid by human yeast-expressed cytochromes P-450 2C8, 2C9, 2C18, and 2C19. Evidence that this drug is a mechanism-based inhibitor specific for cytochrome P-450 2C9, Application In Synthesis of 40180-04-9, the main research area is tienilic acid metabolism liver microsome; cytochrome P450 tienilic acid metabolism.

Oxidation of tienilic acid by human cytochromes P 450 (CYP) 2C9, 2C18, 2C8, and 2C19 was studied using recombinant enzymes expressed in yeast. CYP 2C9 was the best catalyst for 5-hydroxylation of tienilic acid (Km = 5 μM, kcat = 1.7 min ‘), 30-fold more potent in terms of kcat/Km than CYP 2C18 (Km = 150 μM, kcat = 1.8 min ‘) and 300-fold more potent than CYP 2C8 (Km = 145 μM, kcat = 0.2 min-1). CYP 2C19 was unable to catalyze this hydroxylation under our exptl. conditions. A marked effect of the ionic strength on the activities (hydroxylations of tienilic acid and tolbutamide) of these cytochromes P 450 expressed in the yeast strain 334 was observed The effect was particularly great in the case of CYP 2C18, with a tenfold decrease of activity upon increasing ionic strength from 0.02 to 0.1. Specific-covalent binding of tienilic acid metabolites to cytochrome P 450 was markedly higher upon tienilic acid oxidation by CYP 2C9 than by CYP 2C18 and CYP 2C8. Mechanism-based inactivation of cytochrome P 450 during tienilic acid oxidation was observed in the case of CYP 2C9 but was not detectable with CYP 2C18 and CYP 2C8. Tienilic acid thus appears to be a mechanism-based inhibitor specific for CYP 2C9 in human liver. Experiments performed with human liver microsomes confirmed that tienilic acid 5-hydroxylase underwent a time-dependent inactivation during 5-hydroxylation of tienilic acid.

European Journal of Biochemistry published new progress about Enzyme kinetics. 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

Lopez Garcia, M. Pilar published the artcileHuman liver cytochromes P-450 expressed in yeast as tools for reactive-metabolite formation studies. Oxidative activation of tienilic acid by cytochromes P-450 2C9 and 2C10, SDS of cas: 40180-04-9, the main research area is oxidative activation tienilic acid cytochrome yeast; Saccharomyces cytochrome P 450 tienilic acid.

Human liver cytochromes P 450 (P 450) 2C9 and 2C10 expressed in yeast reproduce all the metabolic features of the oxidation of tienilic acid (2-aryloxo-thiophene) and its isomer (3-aroylthiophene) by human liver microsomes. Microsomes of yeast expressing either P 450 2C9 or P 450 2C10 catalyze (a) the 5-hydroxylation of tienilic acid by NADPH and O2 (Km = 6 μM, Vmax = 2.5 turnover/min), (b) the activation of tienilic acid and its isomer into electrophilic metabolites which covalently bind to proteins, and (c) the formation of a mercaptoethanol adduct which results from the trapping of the tienilic acid isomer sulfoxide by this thiol. Microsomes of yeast expressing human liver P 450 3A4, 1A1 and 1A2 are unable to catalyze these reactions. There is a striking similarity between the quant. characteristics of the oxidation of tienilic acid (and its isomer) by yeast-expressed P 450 2C9 (or 2C10) and by human liver microsomes: (a) analogous Km values (around 10 μM) for tienilic acid 5-hydroxylation, (b) a strong inhibition of tienilic acid oxidation by human sera containing anti-(liver kidney microsomes type 2) (anti-LKM2) antibodies, and (c) almost identical relative ratios of tienilic acid metabolic activation/5-hydroxylation and of tienilic acid activation/the activation of its isomer with both systems. Rates of oxidation of tienilic acid (and its isomer) by yeast microsomes are 6-8-fold higher than those found in human liver microsomes, which would be in agreement with the previously reported amount of P 450 2C9 in human liver. These results not only suggest the important role of P 450 2C9 in the oxidative metabolism of tienilic acid in human liver, but also indicate that the 5-hydroxylation reaction could be a useful marker for P 450 2C9 activity and underline the interest of human liver P 450s expressed in yeast as tools for studying the formation of reactive metabolites.

European Journal of Biochemistry published new progress about Enzyme kinetics. 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