Month: November 2022

Stepan, Antonia F. published the artcileStructural Alert/Reactive Metabolite Concept as Applied in Medicinal Chemistry to Mitigate the Risk of Idiosyncratic Drug Toxicity: A Perspective Based on the Critical Examination of Trends in the Top 200 Drugs Marketed in the United States, Category: benzothiophene, the main research area is review reactive metabolite medicinal chem drug toxicity.

Because of a preconceived notion that eliminating reactive metabolite (RM) formation with new drug candidates could mitigate the risk of idiosyncratic drug toxicity, the potential for RM formation is routinely examined as part of lead optimization efforts in drug discovery. Likewise, avoidance of “”structural alerts”” is almost a norm in drug design. However, there is a growing concern that the perceived safety hazards associated with structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be over exaggerated. In addition, the multifactorial nature of idiosyncratic toxicity is now well recognized based upon observations that mechanisms other than RM formation (e.g., mitochondrial toxicity and inhibition of bile salt export pump (BSEP)) also can account for certain target organ toxicities. Hence, fundamental questions arise such as: When is a mol. that contains a structural alert (RM pos. or neg.) a cause for concern. Could the mol. in its parent form exert toxicity. Can a low dose drug candidate truly mitigate metabolism-dependent and -independent idiosyncratic toxicity risks. In an effort to address these questions, we have retrospectively examined 68 drugs (recalled or associated with a black box warning due to idiosyncratic toxicity) and the top 200 drugs (prescription and sales) in the United States in 2009 for trends in physiochem. characteristics, daily doses, presence of structural alerts, evidence for RM formation as well as toxicity mechanism(s) potentially mediated by parent drugs. Collectively, our anal. revealed that a significant proportion (∼78-86%) of drugs associated with toxicity contained structural alerts and evidence indicating that RM formation as a causative factor for toxicity has been presented in 62-69% of these mols. In several cases, mitochondrial toxicity and BSEP inhibition mediated by parent drugs were also noted as potential causative factors. Most drugs were administered at daily doses exceeding several hundred milligrams. There was no obvious link between idiosyncratic toxicity and physicochem. properties such as mol. weight, lipophilicity, etc. Approx. half of the top 200 drugs for 2009 (prescription and sales) also contained one or more alerts in their chem. architecture, and many were found to be RM-pos. Several instances of BSEP and mitochondrial liabilities were also noted with agents in the top 200 category. However, with relatively few exceptions, the vast majority of these drugs are rarely associated with idiosyncratic toxicity, despite years of patient use. The major differentiating factor appeared to be the daily dose; most of the drugs in the top 200 list are administered at low daily doses. In addition, competing detoxication pathways and/or alternate nonmetabolic clearance routes provided suitable justifications for the safety records of RM-pos. drugs in the top 200 category. Thus, while RM elimination may be a useful and pragmatic starting point in mitigating idiosyncratic toxicity risks, our anal. suggests a need for a more integrated screening paradigm for chem. hazard identification in drug discovery. Thus, in addition to a detailed assessment of RM formation potential (in relationship to the overall elimination mechanisms of the compound(s)) for lead compounds, effects on cellular health (e.g., cytotoxicity assays), BSEP inhibition, and mitochondrial toxicity are the recommended suite of assays to characterize compound liabilities. However, the prospective use of such data in compound selection will require further validation of the cellular assays using marketed agents. Until we gain a better understanding of the pathophysiol. mechanisms associated with idiosyncratic toxicities, improving pharmacokinetics and intrinsic potency as means of decreasing the dose size and the associated “”body burden”” of the parent drug and its metabolites will remain an overarching goal in drug discovery.

Chemical Research in Toxicology published new progress about Biological detoxification. 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

Agatonovic-Kustrin, Snezana published the artcileMolecular Structural Characteristics Important in Drug-HSA Binding, Formula: C13H8Cl2O4S, the main research area is acecainide analgesics antibiotic anticancer protein binding structure activity relationship.

A non-linear quant. structure activity relationship (QSAR) model based on 350 drug mols. was developed as a predictive tool for drug protein binding, by correlating exptl. measured protein binding values with ten calculated mol. descriptors using a radial basis function (RBF) neural network. The developed model has a statistically significant overall correlation value (r > 0.73), a high efficiency ratio (0.986), and a good predictive squared correlation coefficient (q2) of 0.532, which is regarded as producing a robust and high quality QSAR model. The developed model may be used for the screening of drug candidate mols. that have high protein binding data, filtering out compounds that are unlikely to be protein bound, and may assist in the dose adjustment for drugs that are highly protein bound. The advantage of using such a model is that the percentage of a potential drug candidate that is protein bound (PB (%)) can be simply predicted from its mol. structure.

Combinatorial Chemistry & High Throughput Screening published new progress about Analgesics. 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

Zhang, Hao published the artcileAccess to Cyanoimines Enabled by Dual Photoredox/Copper-Catalyzed Cyanation of O-Acyl Oximes, Formula: C6H6OS, the main research area is oxime acyl trimethylsilyl cyanide copper iridium light photoredox cyanation; cyanoimine preparation; hydroxamide acyl trimethylsilyl cyanide copper iridium light photoredox cyanation; cyanoamide preparation.

An efficient strategy for the synthesis of pharmaceutically important and synthetically useful cyanoimines, as well as cyanamides, has been described. This strategy is enabled by dual photoredox/copper-catalyzed cyanation of O-acyl oximes or O-acyl hydroxamides. This state of the art protocol for cyanoimines and cyanamides features readily available starting materials, mild reaction conditions, good functional group tolerance, and operational simplicity. The resultant cyanoimines can be transformed into structurally diverse and functionally important N-containing heterocycles.

Organic Letters published new progress about Cyanamides Role: SPN (Synthetic Preparation), PREP (Preparation). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Formula: C6H6OS.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Guan, Ting published the artcilePhotoredox-catalyzed regio- & stereoselective C(sp2)-H cyanoalkylation of enamides with cycloketone oximes via selective C-C bond cleavage/radical addition cascade, Computed Properties of 1468-83-3, the main research area is cyanoalkyl enamide preparation regioselective diastereoselective green chem; enamide cycloketone oxime Heck type cyanoalkylation photoredox catalyst.

A photoredox-catalyzed regio- and stereoselective Heck-type cyanoalkylation of synthetically prominent enamides R1C(=CH2)N(R2)(R3) (R1 = Ph, thiophen-3-yl, 2H-1,3-benzodioxol-5-yl, etc.; R2 = Ac, Bn; R3 = Bn, Me, cyclohexylmethyl, etc.) with cycloketone oximes I (Y = CH, N; R4 = H, n-C6H13, cyclohexylmethyl, Bn, etc.; R5 = H, Ph, CN, Boc, etc.; n = 1, 2) via selective β-C-C bond scission/selective radical addition cascade is developed, enabling the incorporation of synthetically versatile and pharmaceutically appealing distal cyanoalkyl moieties into enamide scaffolds R1C(N(R2)(R3))=CHCH(R4)Y(R5)(CH2)nCN under mild conditions. The synthetic importance of this methodol. was highlighted by the broad substrate scopes, satisfying functional group compatibilities, excellent regio- and stereoselectivities as well as the versatile and diverse synthetic applications of β-cyanoalkylated enamides.

Green Chemistry published new progress about Bond cleavage catalysts. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Computed Properties of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Shah, Falgun published the artcileSetting clinical exposure levels of concern for drug-induced liver injury (DILI) using mechanistic in vitro assays, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is drug induced liver injury assay hepatotoxicity BSEP mitochondria inhibition; Liver Toxicity Knowledge Base; drug-induced liver injury; plasma exposure; safety margin.

Severe drug-induced liver injury (DILI) remains a major safety issue due to its frequency of occurrence, idiosyncratic nature, poor prognosis, and diverse underlying mechanisms. Numerous exptl. approaches have been published to improve human DILI prediction with modest success. A retrospective anal. of 125 drugs (70 = most-DILI, 55 = no-DILI) from the Food and Drug Administration Liver Toxicity Knowledge Base was used to investigate DILI prediction based on consideration of human exposure alone or in combination with mechanistic assays of hepatotoxic liabilities (cytotoxicity, bile salt export pump inhibition, or mitochondrial inhibition/uncoupling). Using this dataset, human plasma Cmax,total ≥ 1.1 μM alone distinguished most-DILI from no-DILI compounds with high sensitivity/specificity (80/73%). Accounting for human exposure improved the sensitivity/specificity for each assay and helped to derive predictive safety margins. Compounds with plasma Cmax,total ≥ 1.1 μM and triple liabilities had significantly higher odds ratio for DILI than those with single/dual liabilities. Using this approach, a subset of recent pharmaceuticals with evidence of liver injury during clin. development was recognized as potential hepatotoxicants. In summary, plasma Cmax,total ≥ 1.1 μM along with multiple mechanistic liabilities is a major driver for predictions of human DILI potential. In applying this approach during drug development the challenge will be generating accurate estimates of plasma Cmax, total at efficacious doses in advance of generating true exposure data from clin. studies. In the meantime, drug candidates with multiple hepatotoxic liabilities should be deprioritized, since they have the highest likelihood of causing DILI in case their efficacious plasma Cmax,total in humans is higher than anticipated.

Toxicological Sciences published new progress about Drug discovery. 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

Cui, Jianguo published the artcileOxidative umpolung selenocyanation of ketones and arenes: An efficient protocol to the synthesis of selenocyanates, Application In Synthesis of 1468-83-3, the main research area is ketone potassium selenocyanate oxidative umpolung selenocyanation; keto ester potassium selenocyanate oxidative umpolung selenocyanation; arene potassium selenocyanate regioselective oxidative umpolung selenocyanation.

A practical method for the umpolung selenocyanation of aryl ketones, alkyl ketones, β-ketoesters and electron-rich arenes was developed, afforded various selenocyanates in moderate to excellent yields. This transformation proceeded by an oxidative umpolung selenocyanation through nitrogen oxides-mediated electrophilic selenocyanation process. This method is simpler, more efficient, and less costly than precedent methods. Further transformations of the arylselenocyanate was performed to prove the synthetic utility of this methodol.

Tetrahedron published new progress about Keto esters Role: RCT (Reactant), SPN (Synthetic Preparation), RACT (Reactant or Reagent), PREP (Preparation). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Application In Synthesis of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Fourches, Denis published the artcileCheminformatics Analysis of Assertions Mined from Literature that Describe Drug-Induced Liver Injury in Different Species, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is cheminformatics drug toxicity liver injury species difference QSAR model.

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chem. structures is critical to help guide exptl. drug discovery projects toward safer medicines. In this study, the authors have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontol. rules. The authors have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chem. determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. The authors found that the concordance of liver effects was relatively low (∼39-44%) between different species, raising the possibility that species specificity could depend on specific features of chem. structure. Compounds were clustered by their chem. similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, addnl. biol. assertions were identified, which were in line with expectations based on compounds’ chem. similarities. The assertions were further converted to binary annotations of underlying chems. (i.e., liver effect vs. no liver effect), and binary quant. structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of the authors’ knowledge, this is the first study for chem. toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automated text mining with limited manual curation, opening up new opportunities for generating and modeling chem. toxicol. data.

Chemical Research in Toxicology published new progress about Chemoinformatics. 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

Ni, Penghui published the artcileMetal-Free Three-Component Selenopheno[2,3-b]indole Formation through Double C-H Selenylation with Selenium Powder, Recommanded Product: 3-Acetylthiophene, the main research area is aromatic ketone indole selenium iodobromide regioselective selenylation heterocyclization; aryl selenophenoindole preparation.

A facile metal-free entry to novel selenopheno[2,3-b]indole motif was described. The three-component assembly of indoles, aromatic ketones and selenium powder were enabled by the IBr-promoted highly selective double C-H selenylation/annulation. This protocol provided a novel access to a diverse variety of selenopheno[2,3-b]indoles with good efficacy and broad functional group compatibility.

Advanced Synthesis & Catalysis published new progress about Heterocyclic compounds, nitrogen-selenium Role: PRP (Properties), RCT (Reactant), SPN (Synthetic Preparation), RACT (Reactant or Reagent), PREP (Preparation). 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Recommanded Product: 3-Acetylthiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Aleo, Michael D. published the artcileEvaluating the role of multidrug resistance protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is MDR3 inhibition screening drug induced liver injury risk assessment; ABCB4 inhibitor screening drug induced liver injury prognosis.

The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern). Of these tested, 41% of Most-DILI-concern and 47% of No-DILI-concern drugs had MDR3 IC50 values of <50 μM. A better distinction across DILI classifications occurred when systemic exposure was considered where safety margins of 50-fold had low sensitivity (0.29), but high specificity (0.96). Anal. of phys. chem. property space showed that basic compounds were twice as likely to be MDR3 inhibitors as acids, neutrals, and zwitterions and that inhibitors were more likely to have polar surface area (PSA) values of <100 Å2 and cPFLogD values between 1.5 and 5. These descriptors, with different cutoffs, also highlighted a group of compounds that shared dual potency as MDR3 and BSEP inhibitors. Nine drugs classified as Most-DILI-concern compounds (four withdrawn, four boxed warning, and one liver injury warning in their approved label) had intrinsic potency features of <20 μM in both assays, thereby reinforcing the notion that multiple inhibitory mechanisms governing bile formation (bile acid and phospholipid efflux) may confer addnl. risk factors that play into more severe forms of DILI as shown by others for BSEP inhibitors combined with multidrug resistance-associated protein (MRP2, MRP3, MRP4) inhibitory properties. Avoiding phys. property descriptors that highlight dual BSEP and MDR3 inhibition or testing drug candidates for inhibition of multiple efflux transporters (e.g., BSEP, MDR3, and MRPs) may be an effective strategy for prioritizing drug candidates with less likelihood of causing clin. DILI. Chemical Research in Toxicology published new progress about Bile (formation). 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

Das, Pradipta published the artcileDramatic Effect of γ-Heteroatom Dienolate Substituents on Counterion Assisted Asymmetric Anionic Amino-Cope Reaction Cascades, Application In Synthesis of 1468-83-3, the main research area is counterion assisted anionic cascade Mannich reaction Cope rearrangement cyclization.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asym. cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an anti-relationship. For fluoride-substituted nucleophiles, a Mannich/amino-Cope cascade proceeds to afford chiral acyclic products with two new stereocenters in a syn-relationship. Bromide- and chloride-substituted nucleophiles appear to proceed via the same pathway as the fluoride albeit with the added twist of a 3-exo-trig cyclization to yield chiral cyclopropane products with three stereocenters. When this same class of nucleophiles is substituted with a γ-nitro group, the Mannich-initiated cascade is now diverted to a β-lactam product instead of the amino-Cope pathway. These anionic asym. cascades are solvent- and counterion-dependent, with a lithium counterion being essential in combination with ethereal solvents such as MTBE and CPME. By altering the geometry of the imine double bond from E to Z, the configurations at the R1 and X stereocenters are flipped. Mechanistic, computational, substituent, and counterion studies suggest that these cascades proceed via a common Mannich-product intermediate, which then proceeds via either a chair (X = N3, SMe, or SCF3) or boat-like (X = F, Cl, or Br) transition state to afford amino-Cope-like products or β-lactam in the case of X = NO2.

Journal of the American Chemical Society published new progress about Chiral auxiliary. 1468-83-3 belongs to class benzothiophene, name is 3-Acetylthiophene, and the molecular formula is C6H6OS, Application In Synthesis of 1468-83-3.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem