Category: 40180-04-9

Kerremans, A. L. M. published the artcilePharmacokinetic and pharmacodynamic studies of tienilic acid in healthy volunteers, Category: benzothiophene, the main research area is tienilic acid pharmacokinetics pharmacodynamics.

In 8 healthy adult volunteers the plasma and urinary levels of tienilic acid and its alc. metabolite, and plasma and urinary levels of Na, creatinine  [60-27-5] and uric acid  [69-93-2] were measured after oral administration of tienilic acid (I) [40180-04-9] 250 mg. A high-performance liquid chromatog. method was developed for the determination of I and its metabolite in plasma and urine. The pharmacokinetic parameters differed only slightly from those reported in the literature, as there was faster absorption and a shorter half-life. I was probably excreted by a saturable renal tubular transport mechanism. The pharmacodynamic effects of tienilic acid developed quickly, showing a uricosuric effect and a moderate natriuretic effect. These effects disappeared in about 8 h. An inverse relationship was found between the starting plasma uric acid level in an individual and the maximal uric acid clearance: the higher the plasma uric acid level, the lower was the maximum effect. Correlation between plasma tienilic acid level and natriuretic effect were seen within individuals and intraindividually. Urinary tienilic acid levels and natriuretic effect were also correlated but only intraindividually. No correlation between drug level and uricosuric effect was found.

European Journal of Clinical Pharmacology published new progress about Blood analysis. 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

Randolph, W. C. published the artcileHigh-pressure liquid chromatographic analysis of ticrynafen and one of its metabolites in urine and serum, Synthetic Route of 40180-04-9, the main research area is ticrynafen blood urine chromatog.

A method is described for the extraction of ticrynafen (I) [40180-04-9], a new hypotensive agent, and its reduced metabolite from serum and urine. Drug-related material is extracted from biol. fluids with ether under strongly acidic conditions and the back-extracted into an alk. aqueous phase, which is subjected to high-pressure liquid chromatog. anal. Separations are performed on a reversed-phase column with a mobile phase consisting of phosphate buffer-acetonitrile. The method measured serum concentrations of I and its reduced metabolite as low as 1.0 and 0.4 μg/mL, resp.

Journal of Pharmaceutical Sciences published new progress about Blood analysis. 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, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Waal-Manning, H. J. published the artcileOne year follow-up of hyperuricemic hypertensive patients treated with tienilic acid or a diuretic with or without uric acid-lowering drugs, Product Details of C13H8Cl2O4S, the main research area is tienilate blood pressure; serum urate tienilate; liver function tienilate.

Fifty-four hypertensive, hyperuricemic patients were pair-matched for age, sex, and current therapy (diuretic, uric acid (I) [69-93-2]-lowering drug) and one member of each pair was assigned to treatment with tienilic acid (II) [40180-04-9] (188 mg/day) while the other member continued on the previous therapy; blood pressure control was equally good in the II-treated and control groups but serum I levels were lower in II-treated patients. Liver function tests changed from pretrial results in 9 patients; minor increases in alk. phosphatase occurred in 8 of these patients (4 in the II treatment group and 4 in the control group). However the 9th patient (receiving II) showed a marked increase in serum aspartate transaminase and eventually rises in alk. phosphatase and bilirubin; these values reverted to normal after stopping II.

Clinical Science published new progress about Blood pressure. 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

Dayan, J. published the artcileApplication of the SOS chromotest to 10 pharmaceutical agents, Quality Control of 40180-04-9, the main research area is drug mutagenesis SOS chromotest assay.

The SOS function-inducing activity of 10 compounds belonging to different chem. classes was studied in Escherichia coli PQ37. The choice of these chems. was based on previously reported mutagenesis studies. This study indicated that 6 compounds which did not induce a pos. response in the Ames test and other mutagenesis tests were also neg. in the SOS chromotest. The other compounds studied had a pos. response in the SOS-inducing function in addition to the pos. results from the Ames test. In order to establish a correlation between these 2 tests a study requiring a larger selection of chem. agents is needed.

Mutation Research, Genetic Toxicology Testing published new progress about DNA SOS repair. 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

Orr, Suvi T. M. published the artcileMechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure-Activity Relationships and Discovery Strategies To Mitigate Drug-Drug Interaction Risks, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome P450 enzyme inhibition drug interaction metabolism SAR.

The importance of mitigating drug-drug interaction (DDI) risks, which arise from inhibition of major human cytochrome P 450 enzymes is a well-established component of the lead optimization process in drug discovery. More recently, there has been much interest in clin. DDIs potentially arising via time- and concentration-dependent cytochrome P 450 inhibition, a phenomenon consistent with mechanism-based inactivation. Inactivated P 450 is catalytically incompetent and must be replenished by newly synthesized protein. Consequently, time-dependent inhibition of P450s presents a greater safety concern compared to reversible inhibition because of the increased propensity for pharmacokinetic interactions upon multiple dosing and the sustained duration of these interactions after discontinuation of the mechanism-based inactivator. Mechanism-based or time-dependent P 450 inhibitors pose an addnl. risk of idiosyncratic drug toxicity since the mechanism of time-dependency often involves the formation of reactive metabolites, which can react with proteins other than the P 450 isoenzyme responsible for catalysis. in vitro time-dependent inhibition (TDI) of P 450 enzymes is now routinely assessed as part of lead optimization efforts in preclin. drug discovery. However, identification of an in vitro TDI liability can raise several questions such as: What is the mechanism of TDI. Does it involve the formation of reactive metabolites. Is there a 1:1 correlation between P 450 TDI and RM formation (as measured from reactive metabolite trapping studies). What is the likelihood that a P 450 time-dependent inhibitor will also cause toxicity. What are the DDI risk mitigation options when dealing with P 450 inactivators in drug discovery – compound progression or termination. Several drugs exhibit in vitro TDI of P 450 enzymes, but only a fraction thereof causes clin. DDIs. Hence, when do we initiate labor-intensive medicinal chem. efforts to design compounds devoid of P 450 TDI liability. What are the best methods to precisely predict the likelihood of occurrence of clin. DDIs with drug candidates that inactivate P 450 enzymes. What are (if any) the qualifying considerations for clin. progression of a P 450 time-dependent inactivator with projected clin. DDI risks. In an effort to address these questions and hopefully provide answers to some of them, we embarked on the present venture wherein we highlight the current state-of-the-art knowledge in this field with a special emphasis on (a) available biochem. and mechanistic approaches in drug discovery to examine TDI of P 450 isoenzymes with new chem. entities, (b) structure-activity relationship studies with marketed drugs associated with DDIs via P 450 inactivation, (c) case studies of medicinal chem. tactics to abrogate P 450 inactivation liability, (d) strategies for progression of P 450 TDI-pos. drug candidates, and (e) the utility of in silico methodol., including the use of physiol.-based pharmacokinetic simulators, in drug discovery to predict the magnitude of clin. DDIs risks anticipated with new clin. candidates.

Journal of Medicinal Chemistry published new progress about Drug discovery. 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

Rana, Payal published the artcileDevelopment of a cell viability assay to assess drug metabolite structure-toxicity relationships, Category: benzothiophene, the main research area is drug metabolite toxicity assay cytochrome P 450 structure toxicity; Cytochrome P450; Drug-induced toxicity; Metabolic activation; Reactive metabolite; Structural alerts.

Many adverse drug reactions are caused by the cytochrome P 450 (CYP)-dependent activation of drugs into reactive metabolites. To reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, the authors developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. The authors screened a series of drugs to explore structural motifs that may be responsible for CYP 450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.

Bioorganic & Medicinal Chemistry Letters published new progress about Drug discovery. 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

Kakutani, Nobuyuki published the artcileNovel risk assessment of reactive metabolites from discovery to clinical stage, Application In Synthesis of 40180-04-9, the main research area is quetiapine rimonabant ritonavir hepatoprotectant drug discovery liver injury; Body burden; Cyanide; Cysteine; Hepatotoxicity; Reactive metabolites; Trapping assay.

This study was aimed to predict drug-induced liver injury caused by reactive metabolites. Reactive metabolites covalently bind to proteins and could result in severe outcomes in patients. However, the relation between the extent of covalent binding and clin. hepatotoxicity is still unclear. From a perspective of body burden (human in vivo exposure to reactive metabolites), we developed a risk assessment method in which reactive metabolite burden (RM burden), an index that could reflect the body burden associated with reactive metabolite exposure, is calculated using the extent of covalent binding, clin. dose, and human in vivo clearance. The relationship between RM burden and hepatotoxicity in humans was then investigated. The results indicated that this RM burden assessment exhibited good predictability for sensitivity and specificity, and drugs with over 10 mg/day RM burden have high-risk for hepatotoxicity. Furthermore, a quant. trapping assay using radiolabeled trapping agents ([35S]cysteine and [14C]KCN) was also developed, to detect reactive metabolite formation in the early drug discovery stage. RM burden calculated using this assay showed as good predictability as RM burden calculated using conventional time- and cost-consuming covalent binding assays. These results indicated that the combination of RM burden and our trapping assay would be a good risk assessment method for reactive metabolites from the drug discovery stage.

Journal of Toxicological Sciences published new progress about Drug discovery. 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

Schuster, Daniela published the artcileDevelopment and validation of an in silico P450 profiler based on pharmacophore models, SDS of cas: 40180-04-9, the main research area is Cytochrome P450 inhibitor pharmacophore model enzyme kinetics.

In today’s drug discovery process, the very early consideration of ADME properties is aimed at a reduction of drug candidate drop out rate in later development stages. A part from in vitro testing, in silico methods are evaluated as complementary screening tools for compounds with unfavorable ADME attributes. Especially members of the cytochrome P 450 (P 450) enzyme superfamily. e.g. P 450 1A2, P 450 2C9, P 450 2C19, P 450 2D6, and P 450 3A4, contribute to xenobiotic metabolism, and compound interaction with one of these enzymes is therefore critically evaluated. Pharmacophore models are widely used to identify common features amongst ligands for any target. In this study, both structure-based and ligand-based models for prominent drug-metabolizing members of the P 450 family were generated employing the software packages LigandScout and Catalyst. Essential chem. ligand features for substrate and inhibitor activity for all five P 450 enzymes investigated were determined and analyzed. Finally, a collection of 11 pharmacophores for substrates and inhibitors was evaluated as an in silico P 450 profiling tool that could be used for early ADME estimation of new chem. entities.

Current Drug Discovery Technologies published new progress about Drug discovery. 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

Liu, Ruifeng published the artcileLocally Weighted Learning Methods for Predicting Dose-Dependent Toxicity with Application to the Human Maximum Recommended Daily Dose, Category: benzothiophene, the main research area is drug toxicity prediction QSAR learning method.

Toxicol. experiments in animals are carried out to determine the type and severity of any potential toxic effect associated with a new lead compound The collected data are then used to extrapolate the effects on humans and determine initial dose regimens for clin. trials. The underlying assumption is that the severity of the toxic effects in animals is correlated with that in humans. However, there is a general lack of toxic correlations across species. Thus, it is more advantageous to predict the toxicol. effects of a compound on humans directly from the human toxicol. data of related compounds However, many popular quant. structure-activity relationship (QSAR) methods that build a single global model by fitting all training data appear inappropriate for predicting toxicol. effects of structurally diverse compounds because the observed toxicol. effects may originate from very different and mostly unknown mol. mechanisms. In this article, we demonstrate, via application to the human maximum recommended daily dose data that locally weighted learning methods, such as k-nearest neighbors, are well suited for predicting toxicol. effects of structurally diverse compounds We also show that a significant flaw of the k-nearest neighbor method is that it always uses a constant number of nearest neighbors in making prediction for a target compound, irresp. of whether the nearest neighbors are structurally similar enough to the target compound to ensure that they share the same mechanism of action. To remedy this flaw, we proposed and implemented a variable number nearest neighbor method. The advantages of the variable number nearest neighbor method over other QSAR methods include (1) allowing more reliable predictions to be achieved by applying a tighter mol. distance threshold and (2) automatic detection for when a prediction should not be made because the compound is outside the applicable domain.

Chemical Research in Toxicology published new progress about Drug screening. 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

Gomez-Lechon, Maria Jose published the artcileMechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project, COA of Formula: C13H8Cl2O4S, the main research area is development innovative hepatotoxicity LIINTOP project.

The 6th European Framework Program project LIINTOP was specifically raised to optimize and provide established protocols and exptl. in vitro models for testing intestinal and liver absorption, metabolism and toxicity of mols. of pharmacol. interest. It has been focused on some of the most promising existing liver and intestine in vitro models with the aim of further improving their performance and thus taking them to a pre-normative research stage. Regarding the specific area of the liver, a first basic approach was the optimization of in vitro hepatic models and the development and optimization of in vitro approaches for toxicity screening. New advanced technologies have been proposed and developed in order to determine cellular and mol. targets as endpoints of drug exposure. A key issue in the development and optimization of in vitro hepatotoxicity screening methods was the selection of structurally diverse suitable hepatotoxic reference model compounds to be tested. To this end, a number of solid selection criteria were defined (drugs preferably than chem. agents, well-documented hepatotoxicity in man and well-defined mechanism/s of hepatotoxicity, com. available no volatile compounds with unequivocal CAS number and chem. structure), the strategy followed, including all resources consulted, is described and the selected compounds are extensively illustrated.

Toxicology in Vitro published new progress about Drug screening. 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