Heterocyclic Building Blocks-Benzothiophene

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

Garay, R. P. published the artcileThe significance of the relative effects of loop diuretics and anti-brain edema agents on the sodium-potassium-chloride cotransport system and the chloride/NaCO3- anion exchanger, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is biol transport diuretic brain edema.

3-Amino-5-sulfamoylbenzoic acids and several series of (aryloxy)alkanoic acids were evaluated for their inhibitory effects on 2 human erythrocyte ion transport systems – the Na+,K+ cotransport system and the DIDS-sensitive anion carrier. Several classic loop diuretics, including the (aryloxy)alkanoic acid ethacrynic acid  [58-54-8] and several 3-amino-5-sulfamoylbenzoic acids, like bumetanide  [28395-03-1] and furosemide  [54-31-9], displayed relatively strong inhibitory activity vs. the cotransport system with relatively weaker action vs. the anion carrier. Furthermore, diuretic potency correlated with cotransport inhibitory potency. Another class of (aryloxy)alkanoic acids, namely the [(2,3-dihydro-1H-inden-5-yl)oxy]acetic acids, such as indacrinone  [56049-88-8] and MK-473  [53108-00-2], which exhibit less potent loop diuretic activity, were less potent cotransport inhibitors and more effective inhibitors of the anion carrier. Still other (aryloxy)alkanoic acids, with little saliuretic activity, namely a subclass of [(2,3-dihydro-1H-inden-5-yl)oxy]alkanoic acids and a series of [(2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acids displayed little or no inhibitory action on the cotransport system but enhanced inhibitory action on the anion carrier. The relative anion carrier inhibitory potency correlated well with the relative inhibitory activity of each compound on bicarbonate-stimulated cell swelling in cat cerebrocortical slices.

Naunyn-Schmiedeberg’s Archives of 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Beaune, Ph. published the artcileImmunotoxicology and expression of human cytochrome P450 in microorganisms, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is autoimmune hepatitis drug cytochrome P450; microorganism human cytochrome P450 expression.

Drug-induced hepatitis can be caused by an abnormal immunol. response. In the case of tienilic acid- and dihydralazine-induced hepatitis, the authors postulated a scheme in which a P 450 produced a reactive metabolite (step 1); this reactive metabolite bound to the P 450 producing it (step 2) leading to a neoantigen triggering the immune response (step 3); the autoantibodies produced during the immune response recognized the P 450 producing the reactive metabolite (step 4). The use of microorganisms (yeast or bacteria) expressing cloned human P 450 helped in proving some steps of this postulated scheme, particularly steps 1 and 4.

Toxicology published new progress about Autoimmune hepatitis. 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

Lopez-Garcia, M. Pilar published the artcileKinetics of tienilic acid bioactivation and functional generation of drug-protein adducts in intact rat hepatocytes, Category: benzothiophene, the main research area is tienilic acid bioactivation protein adduct hepatocyte.

Drug-induced autoimmune hepatitis is among the most severe hepatic idiosyncratic adverse drug reactions. Considered multifactorial, the disease combines immunol. and metabolic aspects, the latter being to date much better known. As for many other model drugs, studies on tienilic acid (TA)-induced hepatitis have evidenced the existence of bioactivation during the hepatic oxidation of the drug, allowing the identification of the neoantigen of anti-LKM2 autoantibodies and the pathway responsible for its formation. However, most of these results are based on the use of microsomal fractions whose relevance to the liver in vivo still needs to be established. In the more complex intact cell environment, several endogenous processes may play a significant role on triggering the reaction and should therefore be considered. In this work the authors have characterized the kinetics of TA biotransformation in metabolically competent hepatocytes, the influence of TA bioactivation on physiol. GSH levels, and the qual. and quant. profile of drug-protein conjugates generated in situ, as a function of exposure time. Results confirm that intact hepatocytes reproduce in vitro the metabolic sequence that leads to the functional generation of drug-protein adducts, in conditions that simulate clin. human exposure to TA. Metabolically competent cultured hepatocytes appear as a very promising approach to investigate the early preimmunol. events of drug-induced autoimmune hepatitis, adequate to identify the conditions that may modulate the formation and specificity of drug-protein adducts in vivo, to study the hepatic disposition of the TA-protein targets, and to define the specific role of the hepatocyte in the origin of this adverse reaction.

Biochemical Pharmacology published new progress about Autoimmune hepatitis. 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

Dansette, P. M. published the artcileDrug-induced immunotoxicity, Application In Synthesis of 40180-04-9, the main research area is review drug immunotoxicity liver.

A review with 70 references is given on immune-response-related drug hepatitis. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into 2 categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clin. features are: (a) low frequency; (b) dose independence; (c) typical immune system manifestations such as fever, eosinophilia; (d) delay between the initiation of treatment and onset of the disease; (e) a shortened delay upon rechallenge; and (f) occasional presence of autoantibodies in the blood serum of patients. Such signs were found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms were postulated. (1) The drug is 1st metabolized into a reactive metabolite which binds to the enzyme that generated it. (2) This produces a neo-antigen which, once presented to the immune system, might trigger an immune response characterized by (3) the production of antibodies recognizing both the native and/or the modified protein. (4) Rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Autoimmune hepatitis. 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