Tag: M.W=200-350

Lewis, David F. V. published the artcileModeling human cytochromes P450 for evaluating drug metabolism: an update, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is CYP450 drug metabolism mol modeling QSAR.

Cytochrome P 450 (CYP) enzymes represent the major catalysts for the Phase 1 metabolism of drugs and other xenobiotics in Mammalia, including Homo sapiens. There is considerable current interest in evaluating and, consequently, predicting the metabolic fate of new chem. entities (NCEs) via modeling mol. interactions with P 450 constructs, such that sites of metabolism, particular CYP involvement and binding affinities, can be estimated This paper focuses on the principles for homol. modeling of typical enzyme-substrate interactions within the putative active sites of major P450s associated with drug metabolism in man. It also represents an update on previously published work in this journal /1/.

Drug Metabolism and Drug Interactions published new progress about Drug metabolism. 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

Hernandez-Olmos, Victor published the artcileDiscovery of Irbesartan Derivatives as BLT2 Agonists by Virtual Screening, SDS of cas: 40180-04-9, the main research area is irbesartan derivative preparation screening BLT2 leukotriene receptor agonist.

Leuktriene B4 receptor 2 (BLT2) is a G-protein coupled receptor modulation of which is discussed to be a therapeutic option for healing of intestinal lesions. In this work, new BLT2 agonists were identified by a virtual screening of a repurposing library and in vitro assay of the most promising compounds Irbesartan, an approved type-1 angiotensin II receptor (AT1) antagonist, was identified as a moderate BLT2 agonist. An initial SAR study on the irbesartan scaffold was performed resulting in the discovery of a new potent BLT2 agonist (8f, EC50 = 67.6 nM). Irbesartan and 8f were shown to promote proliferation of epithelial colon cells, an effect which was reversible by a BLT2 antagonist.

ACS Medicinal Chemistry Letters published new progress about Angiotensin II receptor type 1 antagonists. 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

Hutzler, J. Matthew published the artcileMechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (±)-suprofen: a comparison of kinetics and probe substrate selection, Computed Properties of 40180-04-9, the main research area is tienilic acid suprofen metabolism cytochrome P450 2C9 inactivation.

In vitro experiments were conducted to compare kinact, KI and inactivation efficiency (kintact/KI) of cytochrome P 450 (P 450) 2C9 by tienilic acid and (±)-suprofen using (S)-flurbiprofen, diclofenac, and (S)-warfarin as reporter substrates. Although the inactivation of P 450 2C9 by tienilic acid when (S)-flurbiprofen and diclofenac were used as substrates was similar (efficiency of ∼9 mL/min/μmol), the inactivation kinetics were characterized by a sigmoidal profile. (±)-Suprofen inactivation of (S)-flurbiprofen and diclofenac hydroxylation was also described by a sigmoidal profile, although inactivation was markedly less efficient (∼1 mL/min/μmol). In contrast, inactivation of P 450 2C9-mediated (S)-warfarin 7-hydroxylation by tienilic acid and (±)-suprofen was best fit to a hyperbolic equation, where inactivation efficiency was moderately higher (10 mL/min/μmol) and ∼3-fold higher (3 mL/min/μmol), resp., relative to that of the other probe substrates, which argues for careful consideration of reporter substrate when mechanism-based inactivation of P 450 2C9 is assessed in vitro. Further investigations into the increased inactivation seen with tienilic acid relative to that with (±)-suprofen revealed that tienilic acid is a higher affinity substrate with a spectral binding affinity constant (Ks) of 2 μM and an in vitro half-life of 5 min compared with a Ks of 21 μM and a 50 min in vitro half-life for (±)-suprofen. Lastly, a close analog of tienilic acid with the carboxylate functionality replaced by an oxirane ring was devoid of inactivation properties, which suggests that an ionic binding interaction with a pos. charged residue in the P 450 2C9 active site is critical for recognition and mechanism-based inactivation by these close structural analogs.

Drug Metabolism and Disposition published new progress about Enzyme kinetics. 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

Lewis, David F. V. published the artcileQuantitative structure-activity relationships (QSARs) within substrates of human cytochromes P450 involved in drug metabolism, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is QSAR cytochrome P450 substrate drug metabolism free energy.

The results of quant. structure-activity relation (QSAR) analyses are reported for structurally diverse series of chems. which act as substrates or inhibitors for human hepatic microsomal cytochromes P 450 (CYP). In particular, this study focuses on the major catalysts of drug metabolism in man, namely CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. It is found that good correlations (with correlation coefficients ranging from R = 0.94 to 0.99) with P 450 binding affinity (Km and KD) or competitive inhibition (Ki) values are obtained in each case, especially when consideration of hydrogen bonding parameters are included in the QSAR anal., together with the number of π-π stacking interactions.

Drug Metabolism and Drug Interactions published new progress about Free energy of 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Yamazoe, Yasushi published the artcileConstruction of a fused grid-based template system of CYP2C9 and its application, COA of Formula: C13H8Cl2O4S, the main research area is CYP2C9 grid template system application; CYP2C9-Mediated metabolism; Fused-grid template; Inhibition and enhancement; Poor and good substrates; Simulation of ligand-interaction on template.

A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. CYP2C9 Template generated has been developed as an evaluation system of CYP2C9 metabolism with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with exptl. results suggested a unified way of the interaction of CYP2C9 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C9 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall. Both the walls were separated by a distance corresponding to 1.5-Ring (grid) diameter size, which was termed as Width-gauge. The results indicate that ligand sittings are stabilized through contacts with Facial-wall and the left-side border of Template including specific Position 29 or Left-end after Trigger-residue movement. In addition, Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then initiate CYP2C9 reactions. Simulation experiments for over 500 reactions of CYP2C9 ligands supported the system established. Possible modes of enhanced catalyzes in bi-mol. bindings are also discussed.

Drug Metabolism and Pharmacokinetics published new progress about Drug metabolism. 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

Kahma, Helina published the artcileAn automated cocktail method for in vitro assessment of direct and time-dependent inhibition of nine major cytochrome P450 enzymes – application to establishing CYP2C8 inhibitor selectivity, SDS of cas: 40180-04-9, the main research area is cocktail method time dependent cytochrome enzyme inhibitor selectivity; Cytochrome P450; Drug metabolism; Gemfibrozil 1-O-β-glucuronide; Metabolic interactions; Substrate cocktail; Time-dependent inhibition.

We developed an in vitro high-throughput cocktail assay with nine major drug-metabolizing CYP enzymes, optimized for screening of time-dependent inhibition. The method was applied to determine the selectivity of the time-dependent CYP2C8 inhibitors gemfibrozil 1-O-β-glucuronide and clopidogrel acyl-β-D-glucuronide. In vitro incubations with CYP selective probe substrates and pooled human liver microsomes were conducted in 96-well plates with automated liquid handler techniques and metabolite concentrations were measured with quant. UHPLC-MS/MS anal. After determination of inter-substrate interactions and Km values for each reaction, probe substrates were divided into cocktails I (tacrine/CYP1A2, bupropion/CYP2B6, amodiaquine/CYP2C8, tolbutamide/CYP2C9 and midazolam/CYP3A4/5) and II (coumarin/CYP2A6, S-mephenytoin/CYP2C19, dextromethorphan/CYP2D6 and astemizole/CYP2J2). Time-dependent inhibitors (furafylline/CYP1A2, selegiline/CYP2A6, clopidogrel/CYP2B6, gemfibrozil 1-O-β-glucuronide/CYP2C8, tienilic acid/CYP2C9, ticlopidine/CYP2C19, paroxetine/CYP2D6 and ritonavir/CYP3A) and direct inhibitor (terfenadine/CYP2J2) showed similar inhibition with single substrate and cocktail methods. Established time-dependent inhibitors caused IC50 fold shifts ranging from 2.2 to 30 with the cocktail method. Under time-dependent inhibition conditions, gemfibrozil 1-O-β-glucuronide was a strong (>90% inhibition) and selective (<< 20% inhibition of other CYPs) inhibitor of CYP2C8 at concentrations ranging from 60 to 300μM, while the selectivity of clopidogrel acyl-β-D-glucuronide was limited at concentrations above its IC80 for CYP2C8. The time-dependent IC50 values of these glucuronides for CYP2C8 were 8.1 and 38μM, resp. In conclusion, a reliable cocktail method including the nine most important drug-metabolizing CYP enzymes was developed, optimized and validated for detecting time-dependent inhibition. Moreover, gemfibrozil 1-O-β-glucuronide was established as a selective inhibitor of CYP2C8 for use as a diagnostic inhibitor in in vitro studies. European Journal of Pharmaceutical Sciences published new progress about Animal gene, CYP2D6 Role: BSU (Biological Study, Unclassified), 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

Murayama, Norie published the artcileAssessment of multiple cytochrome P450 activities in metabolically inactivated human liver microsomes and roles of P450 2C isoforms in reaction phenotyping studies, COA of Formula: C13H8Cl2O4S, the main research area is cytochrome P450 liver microsome phenotype; celecoxib; diclofenac; omeprazole; troglitazone; warfarin.

The fraction of substrate metabolized (fm) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Com. available human liver microsomes were recently developed in which one cytochrome P 450 (P 450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P 450 2C isoforms in the depletion and oxidation of probe substrates. Determination of CLint with sets of control and P 450 2C9-inactivated liver microsomes yielded fm,P4502C9 values of 0.69-1.0 for celecoxib, diclofenac and warfarin. Selectively inactivated liver microsomes were thereby shown to be potentially useful for determining the in vitro fm values for major P 450 2C9 contributions to substrate oxidations R-, S- and racemic omeprazole and troglitazone oxidation activities by liver microsomes at multiple substrate concentrations were suppressed by 26-36% and 22-50%, resp., when P 450 2C19- and 2C8-inactivated liver microsomes were used in place of control liver microsomes. This study provides important information to help elucidate the different roles of P 450 isoforms in metabolite formation at different substrate concentrations The data obtained allow the fractions metabolized to be calculated for victim drugs.

Biopharmaceutics & Drug Disposition published new progress about Animal gene, CYP3A4 Role: BSU (Biological Study, Unclassified), 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, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Miyaji, Yoshihiro published the artcileIn vitro evaluation of the potential for drug-induced toxicity based on 35S-labeled glutathione adduct formation and daily dose, COA of Formula: C13H8Cl2O4S, the main research area is liver microsome drug toxicity glutathione.

Background: Drug-induced toxicity such as idiosyncratic drug toxicity is believed to be reduced when either reactive metabolite formation or exposure to a drug is minimized. The objective of the present study was therefore to clarify the relationship between the daily doses, the formation rates of reactive metabolite adduct with 35S-glutathione (RM-GS) and the safety profiles of compounds Results: The RM-GS formation rates for 113 test compounds were determined by incubation with human liver microsomes, and the test compounds were classified into three categories of safe, warning and withdrawn/black box warning. A total of 23 out of 28 withdrawn/black box warning drugs showed both a RM-GS formation rate of over 1 pmol/30 min/mg protein and a dose of over 100 mg. Conclusion: These results suggest that when compounds are plotted in this region, the compounds would have a relatively high idiosyncratic drug toxicity potential.

Bioanalysis published new progress about Addition compounds Role: BSU (Biological Study, Unclassified), 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, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Chen, Nancy published the artcileIn vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes, Quality Control of 40180-04-9, the main research area is budesonide drug interaction transporter cytochrome enzyme inhibition; Budesonide; cytochrome P450 enzymes; drug metabolism; drug transporters; drug–drug interactions; glucocorticoid; human hepatocytes; human liver microsomes.

1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P 450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs).2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A.3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance.4. Collectively, our data indicate there is a low risk of budesonide perpetrating clin. DDIs mediated by the transporters or CYPs studied.

Xenobiotica published new progress about Cation transporters Role: BSU (Biological Study, Unclassified), 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, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Burckhardt, Birgitta Christina published the artcileElectrophysiologic characterization of an organic anion transporter cloned from winter flounder kidney (fROAT), Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is flounder kidney anion transporter; sequence Pseudopleuronectes anion transporter.

The 2-electrode voltage clamp technique was used to demonstrate translocation of p-aminohippurate (PAH) and related compounds such as loop diuretics in Xenopus laevis oocytes expressing the renal organic anion transporter from winter flounder kidney (fROAT). In fROAT-expressing oocytes, PAH (0.1 mM) induced a depolarization of 4.2 mV and at a holding potential of -60 mV an inward current of -22.6 nA. PAH-induced current and the current calculated from [3H]PAH uptake were of similar magnitude. Depolarization, inward current, and current-to-uptake relation indicated exchange of the monovalent PAH with a divalent anion, possibly α-ketoglutarate (α-KG), causing net efflux of 1 neg. charge. The kinetic anal. of PAH-induced currents revealed that translocation is dependent on membrane potential, saturable with an apparent Km of 58 μM, and sensitive to probenecid and furosemide. In contrast to probenecid and furosemide, the loop diuretics bumetanide, ethacrynic acid, and tienilic acid and the nephrotoxic mycotoxin ochratoxin A elicited inward currents indicating translocation through fROAT. Substrate-dependent currents provide a tool to elucidate the structure/function relationship of the renal organic anion transporter.

Journal of the American Society of Nephrology published new progress about Anion transporters Role: BAC (Biological Activity or Effector, Except Adverse), BSU (Biological Study, Unclassified), PRP (Properties), 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, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem