Category: 40180-04-9

Masubuchi, Yasuhiro published the artcileToxicological significance of mechanism-based inactivation of cytochrome P450 enzymes by drugs, Category: benzothiophene, the main research area is review cytochrome terfenadine astemizole griseofulvin tienilic acid dihydralazine.

Cytochrome P 450 (P 450) enzymes oxidize xenobiotics into chem. reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Many clin. important drugs are mechanism-based inactivators that include macrolide antibiotics, calcium channel blockers, and selective serotonin uptake inhibitors, but are not always structurally and pharmacol. related. The inactivation of P450s during drug therapy results in serious drug interactions, since irreversibility of the binding allows enzyme inhibition to be prolonged after elimination of the causal drug. The inhibition of the metabolism of drugs with narrow therapeutic indexes, such as terfenadine and astemizole, leads to toxicities. On the other hand, the fate of P450s after the inactivation and the toxicol. consequences remains to be elucidated, while it has been suggested that P450s modified and degraded are involved in some forms of tissue toxicity. Porphyrinogenic drugs, such as griseofulvin, cause mechanism-based heme inactivation, leading to formation of ferrochelatase-inhibitory N-alkylated protoporphyrins and resulting in porphyria. Involvement of P 450-derived free heme in halothane-induced hepatotoxicity and catalytic iron in cisplatin-induced nephrotoxicity has also been suggested. Autoantibodies against P450s have been found in hepatitis following administration of tienilic acid and dihydralazine. Tienilic acid is activated by and covalently bound to CYP2C9, and the neoantigens thus formed activate immune systems, resulting in the formation of an autoantibody directed against CYP2C9, named anti-liver/kidney microsomal autoantibody type 2, whereas the pathol. role of the autoantibodies in drug-induced hepatitis remains largely unknown.

Critical Reviews in Toxicology published new progress about 5-HT reuptake 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, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Verbitskiy, Egor V. published the artcileSynthesis, and structure-activity relationship for C(4) and/or C(5) thienyl substituted pyrimidines, as a new family of antimycobacterial compounds, Safety of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is thienyl pyrimidine preparation antimycobacterial agent crystal structure; Antimicobacterial; Cross-coupling; Nucleophilic aromatic substitution of hydrogen; Pyrimidine; Tuberculosis.

Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SHN) reactions proved to be a convenient method for the synthesis of C(4) and/or C(5) mono(thienyl) and di(thienyl) substituted pyrimidines from com. available 5-bromopyrimidine. All new pyrimidines are active in micromolar concentrations in vitro against H37Rv, avium, terrae, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The data for acute in vivo toxicity in mice were obtained for these compounds which appear to be promising antitubercular agents.

European Journal of Medicinal Chemistry published new progress about Antimycobacterial agents. 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

Mori, K. published the artcileCocktail-substrate assay system for mechanism-based inhibition of CYP2C9, CYP2D6, and CYP3A using human liver microsomes at an early stage of drug development, Synthetic Route of 40180-04-9, the main research area is cocktail substrate assay cytochrome P450 liver microsome drug development.

1. We established a mechanism-based inhibition cocktail-substrate assay system using human liver microsomes and drugprobe substrates that enabled simultaneous estimation of the inactivation of main cytochrome P 450 (CYP) enzymes, CYP2C9, CYP2D6, and CYP3A, in drug metabolism 2. The inactivation kinetic parameters of typical mechanism-based inhibitors, tienilic acid, paroxetine, and erythromycin, for each enzyme in the cocktail-substrate assay were almost in agreement with the values obtained in the single-substrate assay. 3. Using this system, we confirmed that multiple CYP inactivation caused by mechanism-based inhibitors such as isoniazid and amiodarone could be detected simultaneously. 4. Mechanism-based inhibition potency can be estimated by the determination of the observed inactivation rate constants (kobs) at a single concentration of test compounds because the kobs of eleven CYP3A inactivators at 10×M in the assay system nearly corresponded to kinact/KI values, an indicator of a compound’s propensity to alter the activity of a CYP in vivo (R2 = 0.97). 5 Therefore, this cocktail-substrate assay is considered to be a powerful tool for evaluating mechanism-based inhibition at an early stage of drug development.

Xenobiotica published new progress about Combination chemotherapy. 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

Freitas, R. F. published the artcileNovel Application of 2D and 3D-Similarity Searches To Identify Substrates among Cytochrome P450 2C9, 2D6, and 3A4, Product Details of C13H8Cl2O4S, the main research area is similarity search cytochrome P 450 2C9 2D6 3A4 substrate.

Cytochrome P 450 (CYP450) is a class of enzymes where the substrate identification is particularly important to know. It would help medicinal chemists to design drugs with lower side effects due to drug-drug interactions and to extensive genetic polymorphism. Herein, the application of the 2D and 3D-similarity searches in identifying reference structures with higher capacity to retrieve substrates of three important CYP enzymes (CYP2C9, CYP2D6, and CYP3A4) is discussed. On the basis of the complementarities of multiple reference structures selected by different similarity search methods, it is proposed that their individual Tanimoto scores be fused into a consensus Tanimoto score (Tconsensus). Using this new score, true pos. rates of 63% (CYP2C9) and 81% (CYP2D6) were achieved with false pos. rates of 4% for the CYP2C9-CYP2D6 data set. Extended similarity searches were carried out on a validation data set, and the results showed that by using the Tconsensus score, not only the area of a ROC graph increased, but also more substrates were recovered at the beginning of a ranked list.

Journal of Chemical Information and Modeling published new progress about Drug screening, virtual. 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

Mancy, Annah published the artcileInteraction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9, Product Details of C13H8Cl2O4S, the main research area is cytochrome P450 sulfaphenazole substrate binding site.

The effects of sulfaphenazole (I) on typical activities catalyzed by human cytochromes P 450 of the 1A, 3A, and 2C subfamilies expressed in yeast were studied. I acts as a strong, competitive inhibitor of CYP 2C9 (Ki = 0.3 ± 0.1 μM); it is much less potent toward CYP 2C8 and 2C18 (Ki = 63 and 29 μM, resp.) and fails to inhibit CYP 1A1, 1A2, 3A4, and 2C19. From difference visible spectroscopy experiments using microsomes of yeast expressing various human P450s, I selectively interacts only with CYP 2C9 with the appearance of a peak at 429 nm as expected for the formation of a P 450 Fe(III)-nitrogenous ligand complex (Ks = 0.4 ± 0.1 μM). Comparative studies of the spectral interaction and inhibitory effects of twelve compounds related to I with CYP 2C9 showed that the aniline function of I is responsible for the formation of the iron-nitrogen bond of the 429 nm-absorbing complex and is necessary for the inhibitory effects of I. The study of two new compounds synthesized during this work, in which the N-Ph group of I was replaced with either an Et group or a 3,4-dichlorophenyl group, showed that the presence of an hydrophobic substituent at position I of the pyrazole function of I is required for a strong interaction with CYP 2C9. A model for the binding of I in the CYP 2C9 active site is proposed; that takes into account three major interactions that should be at the origin of the high-affinity and specific inhibitory effects of I toward CYP 2C9: (i) the binding of its nitrogen atom to CYP 2C9 iron, (ii) an ionic interaction of its SO2N- anionic site with a cationic residue of CYP 2C9, and (iii) an interaction of its N-Ph group with an hydrophobic part of the protein active site.

Biochemistry published new progress about Enzyme functional sites. 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

Mancy, Annah published the artcileThe Substrate Binding Site of Human Liver Cytochrome P450 2C9: An Approach Using Designed Tienilic Acid Derivatives and Molecular Modeling, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cytochrome P450 2C9 tienilate derivative association.

Biochem. experiments, using the well-defined human liver CYP2C9 expressed in yeast, and mol. modeling techniques were used to derive a predictive model for substrates of CYP2C9. The ability of 10 2-aroylthiophenes related to tienilic acid to act as substrates for CYP2C9 was studied. Four of them were original compounds that were synthesized and completely characterized by several spectroscopic techniques. In these 10 compounds various chem. functions, such as ester, amide, alc., phenol, ether or tetrazole functions, replaced the OCH2COOH function of tienilic acid. Among them, only the derivatives containing an acidic function (carboxylic acids, phenol, and tetrazole whose pKas are 4.8, 6.3, and 3.8, resp.) underwent a 5-hydroxylation of their thiophene ring like tienilic acid. Despite their close structural analogy with tienilic acid, all of the other compounds not only did not undergo any 5-hydroxylation of their thiophene ring but also failed to act as inhibitors of CYP2C9. These results strongly suggested that the presence, at pH 7.4, of a neg. charge on the substrates is a very important feature in its recognition by CYP2C9. In fact, the four new substrates of CYP2C9 described in this study, a carboxylic acid, phenol, and tetrazole derivative, each of which is related to tienilic acid, and the antiinflammatory drug, suprofen (with Km between 12 and 130 μM and kcat between 0.2 and 1.3 min-1), as well as almost all CYP2C9 substrates reported in the literature, exhibit a pKa below 7 (except phenytoin whose pKa is 8.1). They mainly exist as anions at physiol. pH. By using mol. modeling techniques, 12 CYP2C9 substrates were superimposed with respect to their hydroxylation site and fitted onto templates, which were rigid mols. such as (S)-warfarin and phenytoin. It was thus possible to arrange them in order that all their anionic sites were at a distance around 4 Å from a common point (a putative cationic site of the protein) in space. These results provide a model of the substrate binding site of CYP2C9, in which substrates interact through their anionic site A- with a cationic residue of the CYP2C9 protein C+. In that model, the distance between the hydroxylation site (Hy) and the anionic site (A-) is 7.8 Å, and the ∠HyA-C+ angle is 82°.

Biochemistry published new progress about Enzyme functional sites. 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

Lewis, D. F. V. published the artcileOn the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics. Towards the prediction of human P450 substrate specificity and metabolism, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is mammal microsome cytochrome P450 isoform substrate specificity metabolism.

The characteristics of mammalian microsomal P 450 xenobiotic substrates are described, particularly with reference to the major P 450 isoforms associated with drug metabolism in humans. It is further reported that a relatively small number of mol., electronic, and physico-chem. properties are required to discriminate between chems. that exhibit specificity for human P 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Mol. templates of superimposed substrates are shown to be complementary with the putative active sites of the relevant enzymes, thus enabling a possible prediction of P 450 specificity from structure. Factors contributing to metabolic clearance and binding affinity are also discussed, and methods for their calculation are described.

Biochemical Pharmacology published new progress about Sodium channel blockers. 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

Mansuy, Daniel published the artcileNew biological reactive intermediates. Metabolic activation of thiophene derivatives, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is metabolic activation thiophene derivative review.

A review and discussion with 16 references Metabolic activation of tienilic acid and its isomer, metabolic oxidation of thiophene in vivo and in vitro, inactivation and alkylation of P 450 2C9 upon metabolic activation of tienilic acid, thiophene sulfoxides – a new class of reactive metabolites were discussed.

Advances in Experimental Medicine and Biology published new progress about Biochemical alkylation. 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 of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Pearson, R. M. published the artcileBiochemical and hematological changes induced by tienilic acid combined with propranolol in essential hypertension, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilate propranolol essential hypertension.

In a double blind crossover trial, in which 16 patients with essential hypertension received placebo, tienilic acid (I) [40180-04-9] (250 mg/day), propranolol (II) [525-66-6] (80 mg twice daily), or I (250 mg/day) combined with II (80 mg twice daily), average blood pressure in the lying position was 169/98, 157/94, 159/90, and 142/86 mm Hg for placebo, I-, II-, and I combined with II-treated patients, resp. Thus, the effects of I and II on blood pressure were additive, and no interactions between I and II were observed I reduced serum water from 0.33 to 0.18 mmol/L and induced hypokalemia which was corrected by II. Basophil count and Hb were lower after I treatment than they had been at the start of the study.

Lancet published new progress about Essential hypertension. 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

Lewis, David F. V. published the artcileQuantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is QSAR human cytochrome P450 CYP2 family enzyme.

The results of quant. structure-activity relationship (QSAR) studies on substrates of human CYP2 family enzymes are reported, together with those of a small number of CYP2A6, CYP2C19 and CYP2D6 inhibitors. In general, there are good correlations (R=0.90-0.99) between binding affinity (based on Km or KD values) and various parameters relating to active site interactions such as hydrogen bonding and π-π stacking. There is also evidence for the role of compound lipophilicity (as determined by either log P or log D7.4 values) in overall substrate binding affinity, and this could reflect the desolvation energy involved in substrate interaction within the enzyme active site. It is possible to estimate the substrate binding energy for a given P 450 from a combination of energy terms relating to hydrogen bonding, π-π stacking, desolvation and loss in rotatable bond energy, which agree closely (R=0.98) with exptl. data based on either Km or KD values. Consequently, it is likely that active site interactions represent the major contributory factors to the overall binding affinities for human CYP2 family substrates and, therefore, their estimation is of potential importance for the development of new chem. entities (NCEs) as this can facilitate an assessment of likely metabolic clearance.

Toxicology in Vitro 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