Category: benzothiophene

O’Reilly, Robert A. published the artcileTicrynafen-racemic warfarin interaction: hepatotoxic or stereoselective?, Product Details of C13H8Cl2O4S, the main research area is ticrynafen warfarin interaction stereoselective.

Normal subjects received large single doses of 1.5 mg/kg racemic warfarin (racemic I) [81-81-2] with and without daily oral doses of 250 mg ticrynafen (II) [40180-04-9] beginning 3 days before I and continuing for the duration of hypoprothrombinemia. II induced augmentations of both prothrombin time and plasma I concentration The interaction was evaluated further with separated I enantiomorphs. II induced augmentation of prothrombin times and I concentrations of S-I  [5543-57-7], but had little effect on R-I  [5543-58-8]. Thus, II probably augments the hypoprothrombinemia of racemic I by reducing metabolic clearance of S-I. The lack of effect of II on R-I suggests that the interaction is stereoselective rather than hepatotoxic.

Clinical Pharmacology & Therapeutics (St. Louis, MO, 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, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Schlatter, E. published the artcileEffect of “”high ceiling”” diuretics on active salt transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Correlation of chemical structure and inhibitory potency, Category: benzothiophene, the main research area is diuretic structure kidney salt transport.

The effects of “”high ceiling”” diuretics on the thick ascending limb of the loop of Henle (TAL) and the effect of structure modification on the inhibitory effect of furosemide (I) [54-31-9] on the Na+-2Cl–K+ cotransport system present in the lumen membrane of the TAL were investigated. Isolated cortical TAL (cTAL) segments of rabbit kidneys were perfused in vitro. The equivalent short-circuit current, as a measure of active salt transport, was correlated to the concentration of 64 substances. The results indicated that the so-called “”high ceiling”” or “”loop”” diuretics consist of at least 3 groups: drugs that do not interfere with the active salt transport in the cTAL segment, drugs that interfere by as-yet-uncharacterized mechanisms, and drugs of the furosemide type which inhibit the Na+-2Cl–K+ cotransport system in the lumen membrane of the cTAL segment.

Pfluegers Archiv published new progress about Biological transport. 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

Ullrich, Karl J. published the artcileLuminal transport step of para-aminohippurate (PAH). Transport from PAH-loaded proximal tubular cells into the tubular lumen of the rat kidney in vivo, COA of Formula: C13H8Cl2O4S, the main research area is luminal transport aminohippurate rat kidney; benzoate transport inhibition aminohippurate lumen kidney; uricosuric compound transport inhibition aminohippurate kidney.

Proximal tubular cells were loaded for 10 s with [3H]para-aminohippurate ([3H]PAH) by microperfusing the peritubular capillaries with Ringer solution containing 0.05 mmol/l PAH. Immediately thereafter [3H]PAH influx from cells into a column of equilibrium solution injected into the oil-filled tubular lumen was measured by re-aspirating the fluid after 1-10 s of contact time. The rise of luminal PAH concentration within 2 s of contact time was almost linear, reaching a luminal / capillary concentration ratio of 1.6 after 2 s and of 3.2 after 5 s. The 2-s PAH concentration ratio was not changed when different maneuvers were applied to depolarize proximal tubular cells. Also, the 2-s PAH concentration ratio was not influenced by varying the luminal pH from 6.0 to 8.0 or the luminal Cl- concentration from zero to 134 mmol/l or when either 5 mmol/l urate or 25 mmol/l lactate was in the luminal perfusate. A decrease in the 2-s PAH concentration ratio, i.e. trans-inhibition, was observed when 25 or 50 mmol/l HCO3-(-50%) was in the luminal perfusate. Trans-inhibition was also seen with 5 mmol/l of the following substituted benzoates: 2-hydroxybenzoate (-58%), 2-methoxybenzoate (-46%), 2-hydroxybenzoate acetyl ester (-36%), 2-hydroxy-3,5-dinitrobenzoate (-48%), 3,5-dichlorobenzoate (-49%), and 2,3,5-trichlorobenzoate (-45%). No effect was seen with benzoate, 3-hydroxybenzoate, 2-chlorobenzoate, 2-nitrobenzoate, 2,5-dinitrobenzoate, 3-sulfamoylbenzoate and 4-sulfamoylbenzoate. However, analogs of the latter 2 compounds possessing 2 addnl. side groups, such as furosemide and piretanide, or a hydrophobic moiety, such as probenecid, were inhibitory (by -62, -41 and -49% resp.). Phenoxyacetate had no effect; however, it inhibited if in addition it had 3 chloro groups, as in 2,4,5-trichlorophenoxyacetate (-71%) or a hydrophobic carbamoyl side group, as in mersalylic acid (salyrgan, -75%). Benzene-sulfonate trans-inhibited (-33%), as did phenolsulfonphthalein (phenol red, -39%) and sulfofluorescein (-55%). However, the trans-inhibitory effect of the corresponding carboxy compounds was absent (phenolphthalein) or weaker (fluorescein, -42%). The trans-inhibitory effect of the uricosurics ethacrynic acid (-53%), tienilic acid (-55%) indacrinone (-72%) and benzbromarone (-42%) could be attributed to 2 chloro or bromo side groups on the benzene ring. Other trans-inhibiting uricosuric substances were indomethacin (-42%), sulfinpyrazone (-38%), losartan (-80%) its metabolite EXP 3174 (-55%), and AA 193 (-65%). These organic acids, with pKa values between 2.8 and 4.9, possess chloro and sulfin groups, as well as heterocyclic 5-ring and hydrophobic ring or chain areas. No significant effect was seen with 5 mmol/l PAH, 2-oxo-glutarate, DIDS, cGMP, prostaglandin E2, cortisol, benzylamiloride, pyrazinoic acid, and 25 mmol/l lactate. Our data indicate that in situ the secretory luminal PAH transport proceeds in a nonrheogenic fashion, per exclusionem by anion exchange. The observed trans-inhibition of PAH secretion seems to correlate with the affinity for the luminal PAH transporter and, for uricosuric substances, with their uricosuric potency.

Pfluegers Archiv published new progress about Biological transport. 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

Milton, A. published the artcileRenal tubular accumulation of organic substances: a new in vivo method which differentiates between luminal and peritubular uptake, Computed Properties of 40180-04-9, the main research area is kidney tubule uptake organic compound; radioassay kidney uptake organic compound.

By using a modification of the Sperber technique, cellular uptake of organic substances in the kidney was studied. A test substance was mixed with an extracellular marker (EDTA or inulin), both radiolabeled with an activity ratio close to 1 and injected into the renal portal system on 1 side via a leg vein. The animals were killed 1-10 min after injection and the radioactivity in different organs determined There were significantly higher ipsilateral (injection) to contralateral (control) kidney ratios (substance to marker) at 1 min after injection for Na o-[125I]iodohippurate (125I-Hipp), [14C]tetraethylammonium bromide (14C-TEA), [3H]dihydromorphine (3H-DHM), and [125I]iothalamate, with a progressive decrease in injection kidney ratios for 125I-Hipp and 14C-TEA when death occurred after a longer period. Inhibition of renal tubular transport with novobiocin or mepiperphenidol markedly reduced 1- and 4-min injection kidney ratios for 125I-Hipp and 14C-TEA, resp. When death occurred after a longer period, ratios in both kidneys increased significantly for [125I]iothalamate. A good correlation was found between peak cellular accumulation in the kidney and excretion efficiency of test substances. Thus, the results indicate (1) that 125I-Hipp, [125I]iothalamate, 14C-TEA, and 3H-DHM were accumulated from the peritubular side of the nephron through the transport systems for organic acids and bases, resp., and (2) that [125I]iothalamate also showed luminal uptake. This new in vivo technique is simple and well suited for studying renal tubular accumulation of organic substances and offers the advantage of being able to distinguish luminal from peritubular uptake.

Acta Physiologica Scandinavica published new progress about Biological transport. 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

Prandota, J. published the artcileEffect of tienilic acid (Diflurex) on the binding of 14C-warfarin to human plasma proteins, Product Details of C13H8Cl2O4S, the main research area is tienilate warfarin binding albumin.

Tienilic acid (Diflurex) (I) [40180-04-9], a new diuretic with a chem. structure close to that of ethacrynic acid, displaced significant amounts of warfarin (II) [81-81-2] from human albumin 2 g/L in vitro by a competitive mechanism. No such interaction was observed with physiol. concentrations of human albumin or with human plasma. Because excessive hypoprothrombinemia and hemorrhage were reported in vivo when I was added to oral coumarin anticoagulant therapy, it is advised to use another diuretic if necessary.

International Journal of Clinical Pharmacology, Therapy and Toxicology published new progress about Blood serum albumins. 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

Plessas, C. published the artcileBinding of tienilic acid (Diflurex) to human plasma proteins and erythrocytes, COA of Formula: C13H8Cl2O4S, the main research area is tienilic acid protein binding; erythrocyte tienilic acid binding.

The binding of SKF-62698 (tienilic acid)(Diflurex)(I) [40180-04-9], a new antihypertensive agent with diuretic and uricosuric properties, to human plasma proteins, pure protein fractions, erythrocytes, as well as the effect of heparin [9005-49-6] on the degree of protein binding were measured. Different amounts of I (1 to 1000 μg) were incubated with 1 mL of either human plasma or phosphate buffer M/15 (pH 7.4), containing 47 mg of albumin, at 37° for 2 h. The degree of binding of I to plasma proteins and albumin, at plasma concentration (1-30 μg/mL) of the drug at therapeutic doses, was 99.4-98.5 and 95.8-94.2%, resp. In the case of albumin, a Scatchard plot showed 2 classes of binding sites (M1 = 0.5, K1 = 6.3 × 104/M; M2 = 8, K2 = 2.8 × 103/M). After incubation of 10 μg of drug with 8 mg of α-globulins, 8 mg of β-globulins or 7.4 mg of γ-globulins at 37°, pH 7.4 and ultrafiltration, the degree of binding was 83%, 44%, and 44%, resp. The distribution of I between erythrocytes and plasma ranges between 0.11-0.17 for concentrations of 1 to 15 μg/mL and between 0.17-0.10 for concentrations of 15 to 30 μg/mL under different exptl. conditions, heparin had no effect on the degree of binding of I to plasma proteins.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Blood serum albumins. 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

Prandota, J. published the artcileBinding of tienilic acid (Diflurex) to human serum albumin and to plasma of normal subjects and uremic patients, Quality Control of 40180-04-9, the main research area is tienilate binding plasma protein uremic; serum albumin tienilate binding uremic.

The binding of tienilic acid (TA)(I) [40180-04-9], a new diuretic, to human serum albumin (HSA) and to the plasma of uremic patients under treatment with hemodialysis was measured. At a total concentration of 4.5 μg/mL (expected therapeutic concentration), the unbound fraction of TA to 4% HSA and to normal plasma was 0.49% and 0.6%, resp. The degree of binding was approx. the same from 0.5 to 132 μg/mL of total drug concentration The free fraction of TA increased about 2-fold when total concentration of the drug increased from 0.5 to 192 μg/mL. TA has 2 classes of binding sites. The effect of ionic strength and pH on the binding of TA to HSA indicate that the drug is bound mainly by hydrophobic interaction. Acetylsalicylic acid (300 μg/mL), bilirubin (10 mg%), and palmitic acid (2:1 molar ratio with HSA) decreased TA binding. Reduced drug plasma protein binding was observed in uremic patients. No correlation was found between the unbound fraction of TA and the uremic serum albumin, creatinine, or blood urea concentrations Following an i.v. injection of heparin [9005-49-6], the free fraction of TA in uremic plasma rose from 1.7% to 4.5% after 10 min. of hemodialysis. This could be explained, at least partially, by the increased uremic plasma free fatty acids to albumin molar ratio.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Blood serum albumins. 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

Kaserer, Teresa published the artcileProspective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is virtual drug screening COX inhibitors pharmacophore mol modeling; 2D similarity-based search; Cyclooxygenase; Docking; Method comparison; Pharmacophore modeling; Shape-based modeling.

Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then addnl. predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biol. activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true pos. and true neg. hits, and hitlist composition Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors.

European Journal of Medicinal Chemistry published new progress about Computer application. 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

Grimm, Scott W. published the artcileThe conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective of the Pharmaceutical Research and Manufacturers of America, Synthetic Route of 40180-04-9, the main research area is review conduct drug metabolizing.

Time-dependent inhibition (TDI) of cytochrome P 450 enzymes caused by new mol. entities (NMEs) is of concern because such compounds can be responsible for clin. relevant drug-drug interactions (DDI). Although the biochem. underlying mechanism-based inactivation (MBI) of P 450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clin. DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.

Drug Metabolism and Disposition published new progress about Drug bioavailability. 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

Ma, Chang-Ying published the artcilePrediction models of human plasma protein binding rate and oral bioavailability derived by using GA-CG-SVM method, Synthetic Route of 40180-04-9, the main research area is SVM genetic algorithm protein binding pharmacokinetics.

In this study, support vector machine (SVM) method combined with genetic algorithm (GA) for feature selection and conjugate gradient (CG) method for parameter optimization (GA-CG-SVM), has been employed to develop prediction models of human plasma protein binding rate (PPBR) and oral bioavailability (BIO). The advantage of the GA-CG-SVM is that it can deal with feature selection and SVM parameter optimization simultaneously. Five-fold cross-validation as well as independent test set method were used to validate the prediction models. For the PPBR, a total of 692 compounds were used to train and test the prediction model. The prediction accuracy by means of 5-fold cross-validation is 86% and that for the independent test set (161 compounds) is 81%. These accuracies are markedly higher over that of the best model currently available in literature. The number of descriptors selected is 29. For the BIO, the training set is composed of 690 compounds and external 76 compounds form an independent validation set. The prediction accuracy for the training set by using 5-fold cross-validation and that for the independent test set are 80% and 86%, resp., which are better than or comparable to those of other classification models in literature. The number of descriptors selected is 25. For both the PPBR and BIO, the descriptors selected by GA-CG method cover a large range of mol. properties which imply that the PPBR and BIO of a drug might be affected by many complicated factors.

Journal of Pharmaceutical and Biomedical Analysis published new progress about Drug bioavailability. 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