Day: November 16, 2022

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

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

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 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

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

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

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

Garay, Ricardo P. published the artcileStimulation of potassium fluxes by diuretic drugs in human red cells, COA of Formula: C13H8Cl2O4S, the main research area is diuretic potassium transport erythrocyte.

Two different classes of diuretic drugs consisting of (aryloxy)acetic acid diuretics, including ethacrynic acid  [58-54-8], tienilic acid  [40180-04-9], and (-)-indacrinone  [57297-16-2], and furopyridine diuretics, including (±)-BN 50157 (I) [91868-80-3] and (±)-cycletanide  [89943-82-8], stimulate K+ movement across human red cell membranes. The kinetic properties of this effect (K+-specificity, saturability, optical isomerism, antagonism by structural analogs, etc.) strongly suggest that it is mediated by a K+-transport system with a specific binding site for some diuretic drugs. The stimulated K+ fluxes are resistant to ouabain, bumetanide, and quinine, thus suggesting that they are not mediated by the Na+, K+-pump, Na+, K+-cotransport or by the Ca2+-dependent K+-permeability (Gardos effect). The replacement of Cl- by NO3- ions can either decrease, increase or have no effect on the stimulated K+ fluxes, depending on the diuretic drug. Apparently, the K+ fluxes are not mediated by stimulation of a Cl–dependent K+ carrier. The study of structural analogs of I showed that the intensity of the stimulation of K+ fluxes is strongly correlated with the magnitude of the natriuretic effect. Curiously, some antiallergic furopyridines are able to inhibit K+ fluxes.

Biochemical Pharmacology 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

Maass, Alfred R. published the artcileRenal pharmacology of tienilic acid, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilic acid pharmacol kidney; diuresis tienilic acid; natriuresis tienilic acid.

Tienilic acid (I) [40180-04-9] (10 mg/kg), administered i.v. to hydrated dogs, caused a moderate natriuresis, an increased osmolal clearance, and a neg. free water clearance, whereas I (15 mg/kg, i.v.) administration to hydropenic dogs caused a natriuresis and a diuresis. I resembled hydrochlorothiazide in the pattern of electrolyte response, the maximum natriuresis obtained, the comparable chloruresis, the modest kaliuresis, the prolonged duration of activity and natriuresis in the alkalotic and acidotic dog but differed from hydrochlorothiazide in being uricosuric in the dog. p-Aminohippurate (PAH) inhibited the renal secretion of I, and I inhibited renal PAH secretion. Apparently, the secretion of I is an active process and the site of the natriuretic activity of I is within the lumen of the renal tubule.

Postgraduate Medical Journal, Supplement 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, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Roch-Ramel, Francoise published the artcileEffects of uricosuric and antiuricosuric agents on urate transport in human brush-border membrane vesicles, Related Products of benzothiophene, the main research area is urate transport brush border uricosuric antiuricosuric; kidney brush border urate transport uricosuric.

Inhibition of [14C]-urate uptake by uricosuric and antiuricosuric agents was investigated in human brush-border membrane vesicles, urate being transported either by anion exchange mechanisms or by voltage sensitive pathway. The IC50 for drugs on [14C]-urate uptake in vesicles loaded with 1 mM cold urate or with 5 mM lactate was, resp.: 0.7 and 0.3 μM for benzbromarone; 6 and 4 μM for salicylate; 133 and 13 μM for losartan; 520 and 190 μM for sulfinpyrazone and 807 and 150 μM, for probenecid. The IC50 ratio for [14C]-urate uptake in exchange for cold urate or for lactate varied from about 1 for salicylate to 10 for losartan, supporting the hypothesis that two distinct anion exchangers are involved in urate transport. Application of Hill equation revealed that urate/anion exchangers have more than one binding site, possibly two binding sites with high cooperativity, for benzbromarone and sulfinpyrazone, but only one for probenecid, salicylate and losartan. The uricosuric diuretic, tienilic acid was 10 to 50 times more potent than hydrochlorothiazide, chlorothiazide and furosemide, for inhibiting [14C]-urate uptake in exchange for cold urate. This higher potency is the reason of its uricosuric properties. All uricosuric agents, as well as the antiuricosuric agents, pyrazinoate and ethambutol, had a much lower potency for inhibiting [14C]-urate uptake through the voltage sensitive pathway (apical secretory step) than through the urate/anion exchangers. This suggests that antiuricosuria, induced by pyrazinoate and ethambutol, as well as by low concentrations of uricosuric agents, does not result from an inhibition of the apical voltage sensitive pathway.

Journal of Pharmacology and Experimental Therapeutics 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, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem