Category: benzothiophene

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

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