-
Organic Letters Jun 2024A metal-free and mild approach for constructing 5-amino-1,2-selenazole skeletons by NBS/KSeCN-mediated -selenocyanation and nucleophilic cyclization of β-enaminones has...
A metal-free and mild approach for constructing 5-amino-1,2-selenazole skeletons by NBS/KSeCN-mediated -selenocyanation and nucleophilic cyclization of β-enaminones has been developed. Various isoselenazole compounds and the isoselenazolyl derivatives of anti-inflammatory medicines, including isosepac, oxaprozin, and ibuprofen, have been obtained with good yields. This efficient, "one-pot", and atomic economy strategy may represent an alternative route for the construction of a 1,2-selenazole framework via the "SeCN" pathway and provide new access to heterocycles containing a Se-N bond.
PubMed: 38842460
DOI: 10.1021/acs.orglett.4c01655 -
Liver International : Official Journal... Jun 2024To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI.
OBJECTIVE
To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI.
METHODS
In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort.
RESULTS
Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac.
CONCLUSIONS
Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses.
Topics: Humans; Anti-Inflammatory Agents, Non-Steroidal; Female; Middle Aged; Adult; Aged; Male; Chemical and Drug Induced Liver Injury; United States; Aged, 80 and over; Case-Control Studies; Young Adult; Diclofenac; Risk Factors; Celecoxib
PubMed: 38451034
DOI: 10.1111/liv.15892 -
Journal of Medicinal Chemistry Dec 2023The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference...
The retinoid X receptors (RXRs) are ligand-activated transcription factors involved in, for example, differentiation and apoptosis regulation. Currently used reference RXR agonists suffer from insufficient specificity and poor physicochemical properties, and improved tools are needed to capture the unexplored therapeutic potential of RXR. Endogenous vitamin A-derived RXR ligands and the natural product RXR agonist valerenic acid comprise acrylic acid residues with varying substitution patterns to engage the critical ionic contact with the binding site arginine. To mimic and exploit this natural ligand motif, we probed its structural fusion with synthetic RXR modulator scaffolds, which had profound effects on agonist activity and remarkably boosted potency of an oxaprozin-derived RXR agonist chemotype. Bioisosteric replacement of the acrylic acid to overcome its pan-assay interference compounds (PAINS) character enabled the development of a highly optimized RXR agonist chemical probe.
Topics: Receptors, Retinoic Acid; Ligands; Acrylates; Retinoid X Receptors
PubMed: 38064686
DOI: 10.1021/acs.jmedchem.3c01435 -
Bioinformation 2022Epilepsy is one of the most common neurological disorders, affecting millions of patients with a substantial economic and human burden. About 30-40% of epileptic...
Epilepsy is one of the most common neurological disorders, affecting millions of patients with a substantial economic and human burden. About 30-40% of epileptic patients remain un-treated after the therapeutic option. Genetic or idiopathic epilepsy count about 40% of total epilepsy patients, showing a maximum percentage for drug-resistant epilepsy. Since the last century basic approach to understanding disease progression and drug discovery has been through the prism, exploring all possible causes and treatment options. Here we report about the gene expression-based drug repositioning study for epilepsy. Epilepsy gene expression data was retrieved from the Gene Expression Omnibus database, while drugs-associated gene expression data was retrieved from the Connectivity map (CMAP). The study predicted309 drug compounds which can alter genetic epilepsy-mediated gene signature using an in-house developed R-script. These compounds were docked against identified epilepsy targets- Voltage-gated sodium channel subunit α2 (Nav1.2); GABA receptor α1-β1; and Voltage-gated calcium channel α1G (Cav3.1)using Carbamazepine, Clonazepam, and Pregabalin as standard drugs, respectively. Twenty-one predicted drug compounds showed better binding affinity than respective standards against the selected epileptic receptors. Among these drug compounds, Ergocalciferol, Oxaprozin, Flunarizine, Triprolidine and Cyproheptadine have been previously reported for anti-epileptic activities and can be potential hits to target idiopathic epilepsy.
PubMed: 37654844
DOI: 10.6026/97320630018845 -
Chemico-biological Interactions Sep 2023Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this...
Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide.
Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this characteristic potently attenuate the catalytic function of CYP4A11, drug-drug interactions may occur. Acidic non-steroidal anti-inflammatory drugs (NSAIDs) possess a carboxylic acid in their structure. However, it remains unclear whether these drugs inhibit CYP4A11 activity. The present study examined the inhibitory effects of acidic NSAIDs on CYP4A11 activity using human liver microsomes (HLMs) and recombinant CYP4A11. Sulindac sulfide, ibuprofen, and flurbiprofen effectively decreased the luciferin-4A O-demethylase activity of HLMs and recombinant CYP4A11 (inhibition rates of 30-96% at an inhibitor concentration of 100 μM), while salicylic acid, aspirin, diclofenac, mefenamic acid, indomethacin, etodolac, ketoprofen, loxoprofen, S-naproxen, pranoprofen, zaltoprofen, and oxaprozin exhibited weaker inhibitory activity (inhibition rates up to 23%). Among the drugs tested, sulindac sulfide was the most potent inhibitor of CYP4A11 activity. A kinetic analysis of the inhibition of CYP4A11 by sulindac sulfide revealed mixed-type inhibition for HLMs (K = 3.38 μM) and recombinant CYP4A11 (K = 4.19 μM). Sulindac sulfide is a pharmacologically active metabolite of sulindac (sulfoxide form), which is also oxidized to sulindac sulfone. To elucidate the role of a sulfur atom of sulindac sulfide in the inhibition of CYP4A11, the inhibitory effects of sulindac sulfide and its oxidized forms on CYP4A11 activity were examined. The potency of inhibition against HLMs was greater in the order of sulindac sulfide, sulindac, and sulindac sulfone; IC values were 6.16, 52.7, and 71.6 μM, respectively. The present results indicate that sulindac sulfide is a potent inhibitor of CYP4A11. These results and the molecular modeling of CYP4A11 with sulindac sulfide and its oxidized forms suggest that a sulfur atom of sulindac sulfide as well as its carboxylic acid play important roles in the inhibition of CYP4A11.
Topics: Humans; Sulindac; Carboxylic Acids; Kinetics; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37499995
DOI: 10.1016/j.cbi.2023.110644 -
Journal of the American Chemical Society Aug 2023The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β, = 5730 years) as well as in positron emission...
The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β, = 5730 years) as well as in positron emission tomography (PET) for in vivo molecular imaging applications (carbon-11, β, = 20.4 min). However, the structural diversity of radiotracers is still systematically driven by the narrow available labeled sources and methodologies. In this context, the emergence of carbon dioxide radical anion chemistry might set forth potential unexplored opportunities. Based on a dynamic isotopic equilibration between formate salts and [C, C, C]CO, C-labeled radical anion CO could be accessed under extremely mild conditions within seconds. This methodology was successfully applied to hydrocarboxylation and dicarboxylation reactions in late-stage carbon isotope labeling of pharmaceutically relevant compounds. The relevance of the method in applied radiochemistry was showcased by the whole-body PET biodistribution profile of [C]oxaprozin in mice.
Topics: Mice; Animals; Carbon Isotopes; Carbon Radioisotopes; Carbon Dioxide; Salts; Tissue Distribution; Anions; Positron-Emission Tomography; Formates; Isotope Labeling
PubMed: 37486080
DOI: 10.1021/jacs.3c04679 -
Journal of Inorganic Biochemistry Jun 2023A series of copper(II), nickel(II) and cobalt(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) have been synthesized and characterized by...
A series of copper(II), nickel(II) and cobalt(II) complexes with the non-steroidal anti-inflammatory drug oxaprozin (Hoxa) have been synthesized and characterized by diverse techniques. The crystal structures of two copper(II) complexes, namely the dinuclear complex [Cu(oxa)(DMF)] (1) and the polymeric complex {[Cu(oxa)]·2MeOH·0.5MeOH} (12) were determined by single-crystal X-ray diffraction studies. In order to evaluate in vitro the antioxidant activity of the resultant complexes, their scavenging ability towards 1,1-diphenyl-picrylhydrazyl (DPPH), hydroxyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals was investigated revealing their high effectiveness against these radicals. The binding of the complexes to bovine serum albumin and human serum albumin was examined and the corresponding determined albumin-binding constants showed a tight and reversible interaction. The interaction of the complexes with calf-thymus DNA was monitored by diverse techniques including UV-vis spectroscopy, cyclic voltammetry, DNA-viscosity measurements and competitive studies with ethidium bromide. Intercalation may be proposed as the most possible DNA-interaction mode of the complexes.
Topics: Humans; Oxaprozin; Copper; Coordination Complexes; Anti-Inflammatory Agents, Non-Steroidal; Serum Albumin, Bovine; DNA; Crystallography, X-Ray
PubMed: 36966675
DOI: 10.1016/j.jinorgbio.2023.112196 -
Journal of Medicinal Chemistry Nov 2022Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore...
Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.
Topics: Humans; Binding Sites; Meclofenamic Acid; Oxaprozin; SARS-CoV-2; Viral Nonstructural Proteins; Coronavirus Papain-Like Proteases; COVID-19 Drug Treatment
PubMed: 36356292
DOI: 10.1021/acs.jmedchem.2c01168 -
Molecules (Basel, Switzerland) Sep 2022Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO) for particle engineering. SCCO has great potential...
Over the last years, extensive motivation has emerged towards the application of supercritical carbon dioxide (SCCO) for particle engineering. SCCO has great potential for application as a green and eco-friendly technique to reach small crystalline particles with narrow particle size distribution. In this paper, an artificial intelligence (AI) method has been used as an efficient and versatile tool to predict and consequently optimize the solubility of oxaprozin in SCCO systems. Three learning methods, including multi-layer perceptron (MLP), Kriging or Gaussian process regression (GPR), and k-nearest neighbors (KNN) are selected to make models on the tiny dataset. The dataset includes 32 data points with two input parameters (temperature and pressure) and one output (solubility). The optimized models were tested with standard metrics. MLP, GPR, and KNN have error rates of 2.079 × 10, 2.173 × 10, and 1.372 × 10, respectively, using MSE metrics. Additionally, in terms of R-squared, they have scores of 0.868, 0.997, and 0.999, respectively. The optimal inputs are the same as the maximum possible values and are paired with a solubility of 1.26 × 10 as an output.
Topics: Artificial Intelligence; Carbon Dioxide; Machine Learning; Oxaprozin; Solubility
PubMed: 36144490
DOI: 10.3390/molecules27185762 -
International Journal of Molecular... Sep 2022Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to...
Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs. We aimed to elucidate the promiscuity of FAM drugs on lipid-activated transcription factors and tested 64 approved compounds for activation of RAR, PPARs, VDR, LXR, FXR, and RXR. The activity screening revealed nuclear receptor agonism of several FAM drugs and considerable promiscuity of NSAIDs, while other compound classes evolved as selective. These screening results were not anticipated by three well-established target prediction tools, suggesting that FAMs are underrepresented in bioactivity data for model development. The screening dataset may therefore valuably contribute to such tools. Oxaprozin (RXR), tianeptine (PPARδ), mycophenolic acid (RAR), and bortezomib (RAR) exhibited selective agonism on one nuclear receptor and emerged as attractive leads for the selective optimization of side activities. Additionally, their nuclear receptor agonism may contribute relevant and valuable polypharmacology.
Topics: Fatty Acids; PPAR delta; Receptors, Cytoplasmic and Nuclear; Retinoid X Receptors; Signal Transduction; Transcription Factors
PubMed: 36077469
DOI: 10.3390/ijms231710070