Category: 40180-04-9

Minoletti, Claire published the artcileComparison of the Substrate Specificities of Human Liver Cytochrome P450s 2C9 and 2C18: Application to the Design of a Specific Substrate of CYP 2C18, Synthetic Route of 40180-04-9, the main research area is substrate specificity liver cytochrome P450 2C18; aroylthiophene P450 hydroxylation substrate preparation.

A series of 2-aroylthiophenes derived from tienilic acid by replacement of its OCH2COOH substituent with groups bearing various functions have been synthesized and studied as possible substrates of recombinant human liver cytochrome P450s 2C9 and 2C18 expressed in yeast. Whereas only compounds bearing a neg. charge acted as substrates of CYP 2C9 and were hydroxylated at position 5 of their thiophene ring at a significant rate, many neutral 2-aroylthiophenes were 5-hydroxylated by CYP 2C18 with kcat values of >2 min-1. Among the various compounds that were studied, those bearing an alc. function were the best CYP 2C18 substrates. One of them, compound 3, which bears a terminal O(CH2)3OH function, appeared to be a particularly good substrate of CYP 2C18. It was regioselectively hydroxylated by CYP 2C18 at position 5 of its thiophene ring with a KM value of 9 ± 1 μM and a kcat value of 125 ± 25 min-1, which are the highest described so far for a CYP 2C. A comparison of the oxidations of 3, by yeast-expressed CYP 1A1, 1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, and 3A5, showed that only CYP 2C8, 2C18, and 2C19 were able to catalyze the 5-hydroxylation of 3. However, the catalytic efficiency of CYP 2C18 for that reaction was considerably higher (kcat/KM value being 3-4 orders of magnitude larger than those found for CYP 2C8 and 2C19). Several human P450s exhibited small activities for the oxidative O-dealkylation of 3. The four recombinant CYP 2Cs were the best catalysts for that reaction (kcat between 1 and 5 min-1) when compared to all the P450s that were tested, even though it is a minor reaction in the case of CYP 2C18. All these results show that compound 3 is a new, selective, and highly efficient substrate for CYP 2C18 that should be useful for the study of this P 450 in various organs and tissues. They also suggest some key differences between the active sites of CYP 2C9 and CYP 2C18 for substrate recognition.

Biochemistry published new progress about Hydroxylation, enzymic. 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

Bartoli, Ettore published the artcileUse, misuse and abuse of diuretics, Product Details of C13H8Cl2O4S, the main research area is review diuretics edema body fluid renal hemodynamics; Diuretics; Edema; Hyponatremia; Plasma volume; Renal failure; Renal pathophysiology.

Resolution of edema requires a correct interpretation of body fluids-related renal function, to excrete the excess volume while restoring systemic hemodynamics and avoiding renal failure. In heart failure, the intensive diuresis should be matched by continuous fluids refeeding from interstitium to plasma, avoiding central volume depletion. The slowly reabsorbed ascites cannot refeed this contracted volume in cirrhosis: the ensuing activation of intrathoracic receptors, attended by increased adrenergic and Renin release, causes more avid sodium retention, producing a pos. fluid and Na balance in the face of continuous treatment. High-dose-furosemide creates a defect in tubular Na causing diuresis adequate to excrete the daily water and electrolyte load in Chronic Renal Failure. Diuretic treatment requires care, caution and bedside “”tricks”” aimed at minimizing volume contraction by correctly assessing the homeostatic system of body fluids and related renal hemodynamics.

European Journal of Internal Medicine published new progress about Adrenoceptor agonists. 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

Tanaka, Toshimasa published the artcileCharacterization of the CYP2C8 active site by homology modeling, Quality Control of 40180-04-9, the main research area is CYP2C8 active site homol model pharmacophore CYP2C9 CYP2C19.

To compare the features of the active sites of CYP2C8, CYP2C9, and CYP2C19, homol. modeling was performed based on the crystallog. coordinates of mammalian CYP2C5. It was found that CYP2C8 has a much larger pocket than the other forms due to the existence of an addnl. pocket. The approach to the addnl. pocket is comprised of Ile102, Ser114, Leu208, Val366, and Ile476, and the side chains of Ser114, Val366, and Ile476, which are smaller than the corresponding residues in the other CYPs, enable access to the pocket. The general features of the active site in the CYP2C8 model are similar to those of the previously constructed CYP3A4 model, which may account for the 2 CYPs sharing some of their substrates. The CYP2C8 model was validated by examining the bound orientation of paclitaxel and showing that it is consistent with the formation of the 6-beta hydroxylated derivative during metabolism Docked paclitaxel was found to form a hydrogen bond with the side chain of Asn99, which is a characteristic residue of CYP2C8 and is located in the addnl. pocket. Descriptors for CYP2C8 and CYP2C9 substrates were also examined with the mol. operating environment (MOE). The descriptor by which CYP2C8 and CYP2C9 substrates were classified most distinctly was found to be molar refractivity, which might be related to the longer shape and more polar nature of the active site of CYP2C8 in the CYP2C subfamily.

Chemical & Pharmaceutical Bulletin published new progress about Conformation (homol. model). 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

Pons, Catherine published the artcileDetection of human hepatitis anti-liver kidney microsomes (LKM2) autoantibodies on rat liver sections is predominantly due to reactivity with rat liver P-450 IIC11, SDS of cas: 40180-04-9, the main research area is cytochrome P450 hepatitis autoantibody.

Anti-liver kidney microsomes (anti-LKM2) autoantibodies, appearing in patients treated with tienilic acid and suffering from hepatitis, react with proteins in rat liver sections. The nature of the rat proteins responsible for this recognition and detection of anti-LKM2 has been investigated. Immunoblot testing of the anti-LKM2 with liver microsomes from diversely treated rats and with purified rat liver cytochromes P 450 (IA1, IA2, IIB1, IIB2, IIC6, IIC11 and IVA1) showed that these antibodies cross-reacted with cytochrome P450IIC11 and also with phenobarbital-induced cytochromes P450IIB1 and IIB2. Moreover, metabolic activation of tienilic acid and of a tienilic acid isomer by untreated rat liver microsomes was partially inhibited by anti-LKM2. On the other hand, monospecific polyclonal anti-rat P450IIC11 antibodies cross-reacted with human microsomal cytochromes P 450 and recognized the same cytochromes P 450 as anti-LKM2. This antibody also gave an immunofluorescence pattern on rat and mouse liver and kidney sections very similar to anti-LKM2. The data presented here show that anti-LKM2 recognize epitope shared by rat P 450 IIC11, and a human P 450 of the family IIC. All the results indicate rat P 450 IIC11, the major isoenzyme present in normal adult male rat liver, as the main antigen recognized by human anti-LKM2 autoantibodies; this is the basis of the immunofluorescence test for detection of these antibodies.

Journal of Pharmacology and Experimental Therapeutics published new progress about Autoantibodies Role: BIOL (Biological Study). 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

Bauer, John H. published the artcileEffects of diuretic and propranolol on plasma lipoprotein lipids, Formula: C13H8Cl2O4S, the main research area is diuretic propranolol plasma lipoprotein.

To define the effects of diuretics on plasma lipoproteins, experiments were performed in hypertensive subjects after placebo therapy, 4 wk after therapy with either hydrochlorothiazide (HCTZ)(I) [58-93-5] or ticrynafen (TCNF)(II) [40180-04-9], 3 mo after diuretic with propranolol (III) [525-66-6], and 1 mo after therapy with propranolol alone. Plasma lipoproteins were separated by ultracentrifugation and the lipid fractions isolated by extraction and silicic acid thin-layer chromatog. Plasma low-d. lipoprotein (LDL) total cholesterol fell and high-d. lipoprotein (HDL) total cholesterol rose in subjects receiving TCNF. TCNF had no effect on plasma very low-d. lipoprotein (VLDL) triglyceride or phospholipid. There were no significant changes in LDL or HDL total cholesterol in subjects on HCTZ. HCTZ tended to increase plasma VLDL triglyceride and phospholipid. The addition of propranolol to either diuretic had no effect on LDL or HDL total cholesterol but increased VLDL triglyceride, especially in subjects on HCTZ. Propranolol alone had no effect on any of the lipids measured.

Clinical Pharmacology & Therapeutics (St. Louis, MO, United States) published new progress about Lipoproteins Role: BIOL (Biological Study). 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

Takakusa, Hideo published the artcileQuantitative assessment of reactive metabolite formation using 35S-labeled glutathione, Synthetic Route of 40180-04-9, the main research area is drug metabolism reactive metabolite determination radiolabeled glutathione.

The metabolic bioactivation of a drug to a reactive metabolite (RM) and its covalent binding to cellular macromols. is believed to be involved in clin. adverse events, including idiosyncratic drug toxicities. Therefore, it is important to assess the potential of drug candidates to generate RMs and form drug-protein covalent adducts during lead optimization processes. In this study, the RM formation of some marketed drugs were quant. assessed by means of a sensitive and robust detection method that we have established using 35S-glutathione (35S-GSH) as a trapping agent. Problematic drugs well-known to generate RMs exhibited a relatively high rate of 35S-GS-adducts to RM (RM-GS) formation, which contrasted with safe drugs. For practical use in lead optimization processes, a series of new chem. entities were tested and hints on the structural modifications needed in order to minimize their RM formation were provided. Furthermore, the RM-GS formation rates of a number of compounds were compared using their in vitro covalent binding yields to liver proteins determined with 14C-labeled compounds, demonstrating that the RM-GS formation rate could be a substitute for the covalent binding yield within the same series of compounds

Drug Metabolism and Pharmacokinetics published new progress about Drug metabolism (metabolic bioactivation). 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

Methogo, Ruth Menque published the artcileIdentification of liver protein targets modified by tienilic acid metabolites using a two-dimensional Western blot-mass spectrometry approach, Product Details of C13H8Cl2O4S, the main research area is liver protein tienilic acid metabolite mass spectrometry electrophoresis immunoblotting.

A combined approach based on two-dimensional electrophoresis-immuno-blotting and nanoliquid chromatog. coupled online with electrospray ionization mass spectrometry (nLC-MS/MS) was used to identify proteins modified by a reactive intermediate of tienilic acid (TA). Liver homogenates from rats exposed to TA were fractionated using ultra centrifugation; four fractions were obtained and subjected to 2D electrophoresis. Following transfer to PVDF membranes, modified proteins were visualized after India ink staining, using an anti-serum raised against TA and ECL detection. Immuno-reactive spots were localized on the PVDF membrane by superposition of the ECL image, protein spots of interest were excised, digested on the membrane with trypsin followed by nLC-MS/MS anal. and protein identification. A total of 15 proteins were identified as likely targets modified by a TA reactive metabolite. These include selenium binding protein 2, senescence marker protein SMP-30, adenosine kinase, Acy1 protein, adenosyl-homocysteinase, capping protein (actin filament), protein disulfide isomerase, fumarylacetoacetase, arginase chain A, keto-hexokinase, proteasome endopeptidase complex, triosephosphate isomerase, superoxide dismutase, DNA-type mol. chaperone hsc73 and malate dehydrogenase.

International Journal of Mass Spectrometry published new progress about Autoimmune hepatitis (drug-induced). 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

Bi, Yi-an published the artcileRole of Hepatic Organic Anion Transporter 2 in the Pharmacokinetics of R- and S-Warfarin: In Vitro Studies and Mechanistic Evaluation, Category: benzothiophene, the main research area is warfarin enantiomer liver clearance OAT2 pharmacokinetics pharmacogenomics; CYP2C9; organic anion transporter; pharmacokinetics; physiological based modeling; warfarin.

Interindividual variability in warfarin dose requirement demands personalized medicine approaches to balance its therapeutic benefits (anticoagulation) and bleeding risk. Cytochrome P 450 2C9 (CYP2C9) genotype-guided warfarin dosing is recommended in the clinic, given the more potent S-warfarin is primarily metabolized by CYP2C9. However, only about 20-30% of interpatient variability in S-warfarin clearance is associated with CYP2C9 genotype. We evaluated the role of hepatic uptake in the clearance of R- and S-warfarin. Using stably transfected HEK293 cells, both enantiomers were substrates of organic anion transporter (OAT)2 with a Michaelis-Menten constant (Km) of ∼7-12 μM but did not show substrate affinity for other major hepatic uptake transporters. Uptake of both enantiomers by primary human hepatocytes was saturable (Km ≈ 7-10 μM) and inhibitable by OAT2 inhibitors (e.g., ketoprofen) but not by OATP1B1/1B3 inhibitors (e.g., cyclosporine). To further evaluate the potential role of hepatic uptake in R- and S-warfarin pharmacokinetics, mechanistic modeling and simulations were conducted. A “”bottom-up”” PBPK model, developed assuming that OAT2-CYPs interplay, well recovered clin. pharmacokinetics, drug-drug interactions, and CYP2C9 pharmacogenomics of R- and S-warfarin. Clin. data were not available to directly verify the impact of OAT2 modulation on warfarin pharmacokinetics; however, the bottom-up PBPK model simulations suggested a proportional change in clearance of both warfarin enantiomers with inhibition of OAT2 activity. These results suggest that variable hepatic OAT2 function, in conjunction with CYP2C, may contribute to the high population variability in warfarin pharmacokinetics and possibly anticoagulation end points and thus warrant further clin. investigation.

Molecular Pharmaceutics published new progress about Drug interactions, pharmacokinetic. 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

Bauman, Jonathon N. published the artcileCan In Vitro Metabolism-Dependent Covalent Binding Data Distinguish Hepatotoxic from Nonhepatotoxic Drugs? An Analysis Using Human Hepatocytes and Liver S-9 Fraction, Computed Properties of 40180-04-9, the main research area is hepatotoxic nonhepatotoxic drug liver covalent binding.

In vitro covalent binding studies in which xenobiotics are shown to undergo metabolism-dependent covalent binding to macromols. have been commonly used to shed light on the biochem. mechanisms of xenobiotic-induced toxicity. In this paper hepatotoxins and nonhepatotoxins were tested for their proclivity to demonstrate metabolism-dependent covalent binding to macromols. in human liver S-9 fraction (9000 g supernatant) or human hepatocytes, as an extension to previous work that used human liver microsomes published in this journal [Obachet al. (2008) Chem. Res. Toxicol.21, 1814-1822]. In the S-9 fraction, seven out of the nine drugs in each category demonstrated some level of metabolism-dependent covalent binding. Inclusion of reduced glutathione, cofactors needed by conjugating enzymes, and other parameters (total daily dose and fraction of total intrinsic clearance comprised by covalent binding) improved the ability of the system to sep. hepatotoxins from nonhepatotoxins to a limited extent. Covalent binding in human hepatocytes showed that six out of the nine hepatotoxins and four out of eight nonhepatotoxins demonstrated covalent binding. Taking into account estimates of total daily body burden of covalent binding from the hepatocyte data showed an improvement over other in vitro systems for distinguishing hepatotoxins from nonhepatotoxins; however, this metabolism system still displayed some false positives. Combined with the previous study using liver microsomes, these findings identify the limitations of in vitro covalent binding data for prospective prediction of hepatotoxicity for new drug candidates and highlight the need for a better understanding of the link between drug bioactivation, covalent adduct formation, and toxicity outcomes. Directly relating covalent binding to hepatotoxicity is likely an oversimplification of the process whereby adduct formation ultimately leads to toxicity. Understanding underlying complexities (e.g., which macromols. are important covalent binding targets, interindividual differences in susceptibility, etc.) will be essential to any understanding of the problem of metabolism-dependent hepatotoxicity and predicting toxicity from in vitro experiments

Chemical Research in Toxicology published new progress about Drug metabolism (covalent binding). 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

Klammers, Florian published the artcileEstimation of fraction metabolized by cytochrome P450 enzymes using long-term cocultured human hepatocytes, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is itraconazole antiinflammatory CYP450 enzyme hepatic metabolism.

Estimation of the fraction of a drug metabolized by individual hepatic CYP enzymes relative to hepatic metabolism (fm,CYP) or total clearance h as been challenging for low turnover compounds due to insufficient resolution of the intrinsic clearance (CLint) measurement in vitro and difficulties in quantifying the formation of low abundance metabolites. To overcome this gap, inhibition of drug depletion or selective metabolite formation for 7 marker CYP substrates was investigated using chem. inhibitors and a micro-patterned hepatocyte coculture system (HepatoPac). The use of 3μM itraconazole was successfully validated for estimation of fm,CYP3A4 by demonstration of fm values within a 2-fold of in vivo estimates for 10 out of 13 CYP3A4 substrates in a reference set of marketed drugs. Other CYP3A4 inhibitors (ketoconazole and posaconazole) were not optimal for estimation of fm,CYP3A4 for low turnover compounds due to their high CLint. The current study also demonstrated that selective inhibition sufficient for fm calculation was achieved by inhibitors of CYP1A2 (20μM furafylline), CYP2C8 (40μM montelukast), CYP2C9 (40μM sulfaphenazole), CYP2C19 [3μM (-)N-3-benzyl-phenobarbital], and CYP2D6 (5μM quinidine). Good estimation of fm,CYP2B6 was not possible in this study due to the poor selectivity of the tested inhibitor (20μM ticlopidine). The approach verified in this study can result in an improved fm estimation that is aligned with the regulatory agencies’ guidance and can support a victim drug-drug interaction risk assessment strategy for low clearance discovery and development drug candidates.

Drug Metabolism & Disposition published new progress about Cytochrome P450 CYP2B6 inhibitors. 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