Category: 40180-04-9

Zuniga, Freddi I. published the artcileIdiosyncratic reactions and metabolism of sulfur-containing drugs, Application In Synthesis of 40180-04-9, the main research area is review sulfur containing idiosyncratic drug reaction metabolism toxicity.

Introduction: Idiosyncratic drug reactions (IDRs) that involve the formation of toxic metabolites followed by covalent binding to cellular proteins often go undiscovered until after post-marketing. The goal of this article is to review the current status of IDRs, potential mechanisms and the challenges associated with predicting drug toxicity.Areas covered: The authors review the metabolic pathways of five select classes of sulfur-containing drugs (captopril, troglitazone, tienilic acid, zileuton, methimazole and sudoxicam) suggesting that bioactivation plays a crucial role in the occurrence of IDRs. The reader will gain further awareness that the sulfur atom can propagate as the bioactivation site for the formation of reactive and conceivably toxic metabolites. As such, it is the body’s capacity to detoxify these drug products that may determine whether IDRs occur.Expert opinion: Incomplete understanding of mechanisms culminating in IDR occurrence represents a monumental impediment toward their abrogation. Moreover, current technol. utilized to predict their manifestation (including structure-toxicity relationships) is not infallible and thus, development of novel tools and strategies is indispensible. In an attempt to streamline clin. development and drug approval processes, consortiums have been instated under the US FDA Critical Path Initiative. Collectively, these parameters along with the availability of validated biomarkers and new/updated regulatory guidance could pos. influence the outcome of drug toxicity profiles and direct future drug development.

Expert Opinion on Drug Metabolism & Toxicology published new progress about Drug interactions. 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

Parmentier, Yannick published the artcileDirect and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using the in vitro Silensomes model, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is drug metabolism clearance CYP Silensome; Phenotyping; cytochrome; drug–drug interaction; mechanism based inhibitor; metabolism; microsomes.

We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fmCYP2B6 measured using CYP2B6-Silensomes to adjust the fmCYP2D6.3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolized drugs were well predicted, with 70% within ± 15% accuracy. Moreover, the correlation with observed fmCYP values was higher than that for rhCYPs, which were run in parallel using the same drugs (<45% within ±15% accuracy). Moreover, the choice of the RAF substrate in rhCYP predictions was shown to affect the accuracy of the fmCYP measurement. These results support the use of CYP1A2-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6 and CYP3A4-Silensomes to accurately predict fmCYP values during the in vitro enzyme phenotyping assays in early, as well as in development, phases of drug development. Xenobiotica published new progress about Drug interactions. 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

Dahlinger, Dominik published the artcileDevelopment and validation of an in vitro, seven-in-one human cytochrome P 450 assay for evaluation of both direct and time-dependent inhibition, Formula: C13H8Cl2O4S, the main research area is cytochrome P450 isoform human assay time dependent inhibition validation; Cytochrome P450; Drug–drug interactions; Methods; N-in-one; Single point inactivation; Time-dependent inhibition.

Direct and time-dependent inhibition (TDI) of cytochrome P 450 (CYP) isoforms raises drug safety concerns and has major implications in drug development. This study describes the development of a liquid chromatog.-tandem mass spectrometry (LC-MS/MS)-based screening tool to simultaneously assess both the direct and the time-dependent inhibitory potential of xenobiotics on the 7 major CYPs using a 2-step approach. The in vitro cocktail of FDA-recognized model substrates was incubated with human liver microsomes (HLM) and consisted of caffeine (CYP1A2), bupropion (CYP2B6), rosiglitazone (CYP2C8), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Direct and time-dependent inhibitory profiles of direct and time-dependent reference inhibitors for each CYP were studied. For validation, the results were compared to those obtained with the traditional single substrate approach. Statistical uncertainty was quantified using the bootstrap method. The direct inhibition assay showed an acceptable fold bias of 1.35 (geometric mean fold absolute deviation, range 1.01-2.61) in the IC50 values for the cocktail assay compared to the single substrate results with no trend for under- or overestn. Using a single point inactivation assay to assess TDI, the authors were able to identify all 7 tested time-dependent reference inhibitors, without any false negatives. The presented design enhanced throughput by assessing the 7 major CYPs simultaneously and allowed for the detection of and discrimination between direct and time-dependent CYP inhibition via IC50 and single point inactivation experiments For the latter, a threshold of 10% TDI was proposed for carrying out more detailed inactivation kinetic experiments

Journal of Pharmacological and Toxicological Methods published new progress about Drug interactions. 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

Sekiguchi, Nobuo published the artcilePreclinical evaluation of the potential for cytochrome P450 inhibition and induction of the selective ALK inhibitor, alectinib, Application In Synthesis of 40180-04-9, the main research area is alectinib cytochrome P450 anaplastic lymphoma kinase; CYP2C8; CYP3A4; drug–drug interaction; in vitro; irreversibility; time-dependent inhibition.

1. A novel selective anaplastic lymphoma kinase (ALK) inhibitor, alectinib, has shown remarkable efficacy and safety in patients with ALK-pos. non-small-cell lung cancer (NSCLC). The purpose of this study was to evaluate in vitro the potential to inhibit and induce cytochrome P 450 (CYP) isoforms for alectinib and its major metabolite M4.2. Alectinib and M4 did not show the meaningful direct inhibition of six major CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) in human liver microsomes (HLM). Alectinib, but not M4, competitively inhibited CYP2C8, by which few marketed drugs are exclusively metabolized, with an inhibition constant of 1.98 μM.3. Out of the seven CYP isoforms in HLM, alectinib and M4 showed time-dependent inhibition (TDI) of only CYP3A4, which suggests low TDI potential due to low inactivation efficiency.4. Alectinib exhibited quite smaller induction of mRNA expression of CYP1A2, 2B6 and 3A4 genes in human hepatocytes compared to the resp. pos. controls, suggesting a low potential of enzyme induction.5. In summary, the risk of alectinib causing drug-drug interactions with coadministered drugs is expected to be low due to the weak potential of CYP inhibition and induction estimated in the preclin. studies.

Xenobiotica published new progress about Drug interactions. 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

Lee, Kye Sook published the artcileDirect and metabolism-dependent cytochrome P450 inhibition assays for evaluating drug-drug interactions, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome P450 tidopidine furafylline liver microsome.

We developed methods for evaluating the ntial inhibition of human cytochrome P 450 (CYP) enzymes, including CYP1A2, CYP2A6, CYP2B6, CYP2 C9, CYP2 C19, CYP2D6, CYP2E1 and CYP3A4, using pooled human liver microsomes (HLMs). The CYP inhibition assay used substrate cocktail sets [set A: phenacetin for CYP1A2, coumarin for CYP2A6, (S)-(+)-mephenytoin for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4; set B: bupropion for CYP2B6, tolbutamide for CYP2C9, chlorzoxazone for CYP2E1, and testosterone for CYP3A4] with quantitation by liquid chromatog.-tandem mass spectrometry. A direct inhibition assay was performed with the substrate cocktails without β-NADP (NADPH) pre-incubation, and a metabolism-dependent inhibition (MDI) assay was performed after 30 min of pre-incubation with NADPH in HLMs. MDI was identified based on the half-maximal inhibitory concentration (IC50) shifts. The IC50 values of the direct inhibitors determined using the probe substrate cocktails were in good agreement with previously reported values. Eight metabolism-dependent inhibitors including furafylline, 8-methoxypsoralen, tienilic acid, ticlopidine, fluoxetine, paroxetine, disulfiram and verapamil against CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, resp., resulted in significant IC50 shifts (≥2.5-fold) after pre-incubation. Thus, these CYP inhibition assays are considered to be useful tools for evaluating both direct inhibition and MDI at an early stage of the drug discovery and development process. Copyright © 2011 John Wiley & Sons, Ltd.

Journal of Applied Toxicology published new progress about Drug interactions. 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

Perloff, E. S. published the artcileValidation of cytochrome P450 time-dependent inhibition assays: a two-time point IC50 shift approach facilitates kinact assay design, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome P450 inhibitor liver drug interaction.

Recent guidance from the US Food and Drug Administration (USFDA) has advocated testing of time-dependent inhibition of cytochrome P 450 (CYP), which can be addressed by performing IC50 shift as well as KI/kinact determinations Direct (IC50, Ki) and time-dependent inhibition (IC50 shift, KI/kinact) assays were validated in human liver microsomes with liquid chromatog.-tandem mass spectrometry (LC/MS/MS) anal. for the following enzyme/substrate/inhibitor combinations: CYP1A2/phenacetin/alpha-naphthoflavone/furafylline, CYP2C8/amodiaquine/montelukast/gemfibrozil-1-O-β-glucuronide, CYP2C9/diclofenac/sulfaphenazole/tienilic acid, CYP2C19/S-mephenytoin/S-benzylnirvanol/S-fluoxetine, CYP2D6/dextromethorphan/quinidine/paroxetine, and CYP3A4/midazolam/testosterone/ketoconazole/azamulin/verapamil/diltiazem. IC50 shift assays were performed with two pre-incubation time points (10 and 30 min) to facilitate kinact assay design. Data obtained show good agreement with literature values. For rapid acting inhibitors, such as azamulin/CYP3A4 and tienilic acid/CYP2C9, the IC50 shifts were similar at both time points suggesting a short maximum pre-incubation time with closely spaced time points for the KI/kinact assay. Slow acting inhibitors (such as verapamil/CYP3A4 or S-fluoxetine/CYP2C19) showed an increase in IC50 shift between 10 and 30 min suggesting a longer maximum pre-incubation time with wider spacing of time points for KI/kinact. The two-time point IC50 shift experiment proved to be an excellent method for the selection of appropriate KI/kinact assay parameters and is suitable for the routine anal. of P 450 inhibition by drug candidates.

Xenobiotica published new progress about Drug interactions. 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

Zimmerman, Hyman J. published the artcileEffects of ticrynafen on hepatic excretory function in the isolated perfused rat liver, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is ticrynafen liver toxicity phenobarbital.

Ticrynafen (I) [40180-04-9] impaired the function of the isolated perfused rat liver. At concentrations in the perfusate equivalent to those produced in the blood of man by therapeutic doses, the drug led to a striking reduction in bile flow and sulfobromophthalein excretion and release of aspartate aminotransferase into the perfusate. These adverse effects were enhanced by treatment of rats with phenobarbital  [50-06-6] prior to removal of the liver, indicating that the adverse effect of ticrynafen is probably caused by a metabolite produced in the cytochrome P 450  [9035-51-2] system.

Hepatology (Philadelphia, PA, United States) published new progress about Drug interactions. 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

Rao, Sreedhara published the artcileA Refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions, Computed Properties of 40180-04-9, the main research area is QSAR cytochrome P4502C9 drug interaction CoMFA.

A ligand-based model is reported that predicts the Ki values for cytochrome P 450 2C9 (CYP2C9) inhibitors. This CoMFA model was used to predict the affinity of 14 structurally diverse compounds not in the training set and appears to be robust. The mean error of the predictions is 6 μM. The exptl. measured Ki values of the 14 compounds range from 0.1 to 48 μM. Leave-one-out cross-validated partial least-squares gives a q2 value of between 0.6 and 0.8 for the various models which indicates internal consistency. Random assignment of biol. data to structure leads to neg. q2 values. These models are useful in that they establish a pharmacophore for binding to CYP2C9 that can be tested with site-directed mutagenesis. These models can also be used to screen for potential drug interactions and to design compounds that will not bind to this enzyme with high affinity.

Journal of Medicinal Chemistry published new progress about Drug interactions. 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

Fujioka, Yasushi published the artcileRisk assessment of mechanism-based inactivation in drug-drug interactions, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is risk assessment drug interaction CYP inhibitor model; cytochrome P450 inhibitor drug interaction risk assessment model.

Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P 450 are of serious concern. Although several predictive models have been published, early risk assessment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/Ki ([I], the inhibitor concentration; Ki, the inhibition constant) is widely used in drug discovery and development. Although a simple and reliable methodol. such as [I]/Ki categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive anal. of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term λ/kdeg (λ, 1st-order inactivation rate at a given MBI concentration; kdeg, enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this anal. show that in vivo DDIs with >2-fold change of object drug AUC can be identified with the cutoff value of λ/kdeg = 1, where unbound steady-state Cmax is used for inhibitor concentration However, the use of total Cmax led to great overprediction of DDI risk. The risk assessment using λ/kdeg coupled with unbound Cmax can be useful for the DDI risk evaluation of MBIs in drug discovery and development.

Drug Metabolism & Disposition published new progress about Drug interactions. 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

Belghazi, Maya published the artcileUse of isotopes and LC-MS-ESI-TOF for mechanistic studies of tienilic acid metabolic activation, SDS of cas: 40180-04-9, the main research area is tienilate metabolic activation mechanism cytochrome P 450 2C9.

Tienilic Acid (TA) is a uricosuric drug marketed in 1978 and which caused a number of rare immunoallergic hepatitis. It was withdrawn in the U.S. in 1980, in France in 1992. Early batches of tienilic acid also contained 0.1-0.5 % tienilic acid isomer. Tienilic acid isomer (TAI) has been shown to be metabolized by cytochrome P 450 (CYP) into a reactive thiophene 1-oxide which either binds to proteins, or can be trapped by sulfur nucleophiles. Tienilic acid is metabolized by human CYP 2C9 into 5-hydroxytienilic acid (a major metabolite representing 70 % of the dose excreted in human urine) but it also forms (a) reactive metabolite(s) which binds covalently to CYP 2C9 and it is a mechanism based inhibitor of CYP 2C9. Adding glutathione to incubations decreases the covalent binding, but only to 1 mol/mol P 450. However the reactive metabolite of tienilic acid is still unknown. Recently it has been shown using ESI-LC-MS that CYP 2C9 binds ∼2 mol of TA in absence of GSH and only one in presence of 3 mM GSH. Two pathways of activation of the thiophene ring have been postulated: (A) the arene oxide pathway and (B) the thiophene 1-oxide (or thiophene S-oxide) pathway. In the case of thiophene, benzo(b)thiophene, tienilic acid isomer and several other thiophenes, metabolism through pathway B (thiophene 1-oxide) has been clearly demonstrated. The 1-oxide has only been isolated in the case of benzothiophene. Thus, the aim of the present study was to more carefully examine the metabolic oxidation of tienilic acid using HPLC-MS (LC-ESI-TOF mass spectroscopy) in order to determine which pathway (A or B) is involved in this oxidation For that purpose, labeling experiments with deuterated TA, 1802, 18H2O, and D2O were also performed.

Advances in Experimental Medicine and Biology published new progress about Enzymic oxidation. 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