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Journal of Medicinal Chemistry Dec 2022Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue with an associated metabolic instability liability led to the identification...
Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue (NF54 IC = 0.012 μM; K1 IC = 0.040 μM) displaying high microsomal metabolic stability (HLM CL < 11.6 μL·min·mg) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates efficacy in -infected mice at 4 × 50 mg·kg oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.
Topics: Mice; Animals; Plasmodium berghei; Antimalarials; Astemizole; Plasmodium falciparum; Malaria; Disease Models, Animal
PubMed: 36507890
DOI: 10.1021/acs.jmedchem.2c01516 -
Xenobiotica; the Fate of Foreign... Jul 20221. Cytochrome P450 2J2 (CYP2J2) shows high expression in extrahepatic tissues, including the heart and kidney and in tumours. Inhibition of CYP2J2 has attracted...
1. Cytochrome P450 2J2 (CYP2J2) shows high expression in extrahepatic tissues, including the heart and kidney and in tumours. Inhibition of CYP2J2 has attracted attention for cancer treatment because it metabolises arachidonic acid (AA) to epoxyeicosatrienoic acid (EET), which inhibits apoptosis and promotes tumour growth. Multi-kinase inhibitor (MKI) is a molecular-targeted drug with antitumor activities. This study aimed to clarify the inhibitory effects of MKIs on CYP2J2 activity. We also investigated whether MKIs affected CYP2J2-catalysed EET formation from AA.2. Twenty MKIs showed different inhibitory potencies against astemizole -demethylation in CYP2J2. In particular, apatinib, motesanib, and vatalanib strongly inhibited astemizole -demethylation. These three MKIs exhibited competitive inhibition with inhibition constant () values of 9.3, 15.4, and 65.0 nM, respectively. Apatinib, motesanib, and vatalanib also inhibited CYP2J2-catalysed 14,15-EET formation from AA.3. In simulations of docking to CYP2J2, the energy values of apatinib, motesanib, and vatalanib were low, and measured -84.5, -69.9, and -52.3 kcal/mol, respectively.4. In conclusion, apatinib, motesanib, and vatalanib strongly inhibited CYP2J2 activity, suggesting that the effects of a given CYP2J2 substrate may be altered upon the administration of these MKIs.
Topics: Cytochrome P-450 Enzyme System
PubMed: 36251932
DOI: 10.1080/00498254.2022.2137068 -
International Journal of Molecular... Sep 2022Despite the significant progress made towards comprehending the deregulated signatures in lung cancer, these vary from study to study. We reanalyzed 25 studies from the...
Despite the significant progress made towards comprehending the deregulated signatures in lung cancer, these vary from study to study. We reanalyzed 25 studies from the Gene Expression Omnibus (GEO) to detect and annotate co-deregulated signatures in lung cancer and in single-gene or single-drug perturbation experiments. We aimed to decipher the networks that these co-deregulated genes (co-DEGs) form along with their upstream regulators. Differential expression and upstream regulators were computed using Characteristic Direction and Systems Biology tools, including GEO2Enrichr and X2K. Co-deregulated gene expression profiles were further validated across different molecular and immune subtypes in lung adenocarcinoma (TCGA-LUAD) and lung adenocarcinoma (TCGA-LUSC) datasets, as well as using immunohistochemistry data from the Human Protein Atlas, before being subjected to subsequent GO and KEGG enrichment analysis. The functional alterations of the co-upregulated genes in lung cancer were mostly related to immune response regulating the cell surface signaling pathway, in contrast to the co-downregulated genes, which were related to S-nitrosylation. Networks of hub proteins across the co-DEGs consisted of overlapping TFs (SOX2, MYC, KAT2A) and kinases (MAPK14, CSNK2A1 and CDKs). Furthermore, using Connectivity Map we highlighted putative repurposing drugs, including valproic acid, betonicine and astemizole. Similarly, we analyzed the co-DEG signatures in single-gene and single-drug perturbation experiments in lung cancer cell lines. In summary, we identified critical co-DEGs in lung cancer providing an innovative framework for their potential use in developing personalized therapeutic strategies.
Topics: Adenocarcinoma of Lung; Astemizole; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase 14; Transcription Factors; Valproic Acid
PubMed: 36142846
DOI: 10.3390/ijms231810933 -
International Journal of Molecular... Sep 2022The hEag1 (Kv10.1) K channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion...
The hEag1 (Kv10.1) K channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion channels in osteogenesis, we tested whether pharmacological modulation of hEag1 may affect osteogenic differentiation of osteosarcoma cell lines. Using molecular biology (RT-PCR), electrophysiology (patch-clamp) and pharmacology (astemizole sensitivity, IC = 0.135 μM) we demonstrated that SaOS-2 osteosarcoma cells also express hEag1 channels. SaOS-2 cells also express to KCa1.1 K channels as shown by mRNA expression and paxilline sensitivity of the current. The inhibition of hEag1 (2 μM astemizole) or KCa1.1 (1 mM TEA) alone did not induce Ca deposition in SaOS-2 cultures, however, these inhibitors, at identical concentrations, increased Ca deposition evoked by the classical or pathological (inorganic phosphate, Pi) induction pathway without causing cytotoxicity, as reported by three completer assays (LDH release, MTT assay and SRB protein assay). We observed a similar effect of astemizole on Ca deposition in MG-63 osteosarcoma cultures as well. We propose that the increase in the osteogenic stimuli-induced mineral matrix formation of osteosarcoma cell lines by inhibiting hEag1 may be a useful tool to drive terminal differentiation of osteosarcoma.
Topics: Astemizole; Bone Neoplasms; Cell Line, Tumor; Ether-A-Go-Go Potassium Channels; Humans; Osteogenesis; Osteosarcoma; Phosphates; RNA, Messenger
PubMed: 36142445
DOI: 10.3390/ijms231810533 -
Toxicological Sciences : An Official... Oct 2022Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6...
Validation of Risk-Stratification Method for the Chronic Atrioventricular Block Cynomolgus Monkey Model and Its Mechanistic Interpretation Using 6 Drugs With Pharmacologically Distinct Profile.
Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6 pharmacologically distinct drugs. The following drugs were orally administered in conscious state, astemizole: 1, 5, and 10 mg/kg (n = 6); haloperidol: 1, 10, and 30 mg/kg (n = 5); amiodarone: 30 mg/kg (n = 4); famotidine: 10 mg/kg (n = 4); levofloxacin: 100 mg/kg (n = 4); and tolterodine: 0.2, 1, and 4.5 mg/kg (n = 4). Astemizole of 5 and 10 mg/kg significantly prolonged ΔΔQTcF, whereas no significant change was observed by the others. Torsade de pointes (TdP) was induced by astemizole of 5 and 10 mg/kg in 3/6 and 6/6, and by haloperidol of 10 and 30 mg/kg in 1/5 and 1/5, respectively, which was not observed in the others. Torsadogenic risk of the drugs was quantified using the criteria for the monkey model specified in our previous study. Namely, high-risk drugs induced TdP at ≤ 3 times of their maximum clinical daily dose. Intermediate-risk drugs did not induce TdP at this dose range, but induced it at higher doses. Low/no-risk drugs never induced TdP at any dose tested. The magnitude of risk was intermediate for astemizole and haloperidol, and low/no risk for the others. The prespecified, risk-stratification method for the monkey model may solve the issue existing between nonclinical models and patients with labile repolarization, which can reinforce the regulatory decision-making and labeling at time of marketing application of nondouble-negative drug candidate (hERG assay positive and/or in vivo QT study positive).
Topics: Animals; Atrioventricular Block; Macaca fascicularis; Astemizole; Haloperidol; Torsades de Pointes; DNA-Binding Proteins; Electrocardiography
PubMed: 35993620
DOI: 10.1093/toxsci/kfac088 -
British Journal of Pharmacology Sep 2022HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency...
BACKGROUND AND PURPOSE
HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes.
EXPERIMENTAL APPROACH
Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model.
KEY RESULTS
Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias.
CONCLUSION AND IMPLICATIONS
This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties.
Topics: Animals; Arrhythmias, Cardiac; Dogs; Drug-Related Side Effects and Adverse Reactions; Electrocardiography; Ether-A-Go-Go Potassium Channels; Heart Rate; Long QT Syndrome; Moxifloxacin; Quinidine; Reflex; Torsades de Pointes
PubMed: 35751378
DOI: 10.1111/bph.15905 -
ACS Omega Jun 2022Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are...
Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies.
Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.
PubMed: 35721972
DOI: 10.1021/acsomega.2c00518 -
European Journal of Pharmacology Aug 2022The transient receptor potential (TRP) channel TRPV2 is widely expressed in a variety of different cell types and tissues. However, elucidating the exact biological...
The transient receptor potential (TRP) channel TRPV2 is widely expressed in a variety of different cell types and tissues. However, elucidating the exact biological functions of TRPV2 is significantly hampered by the lack of selective pharmacological tools to modulate channel activity in vitro and in vivo. This study aimed to identify new compounds that modify TRPV2 activity via the use of a plate-based calcium imaging approach to screen a drug repurposing library. Three antihistaminic drugs, loratadine, astemizole and clemizole were identified to reduce calcium-influx evoked by the TRPV2 agonist tetrahydrocannabivarin in HEK293 cells expressing murine TRPV2. Using single-cell calcium-microfluorimetry and whole-cell patch clamp recordings, we further confirmed that all three compounds induced a concentration-dependent block of TRPV2-mediated Ca influx and whole-cell currents, with loratadine being the most potent antagonist of TRPV2. Moreover, this study demonstrated that loratadine was able to block both the human and mouse TRPV2 orthologs, without inhibiting the activity of other closely related members of the TRPV superfamily. Finally, loratadine inhibited TRPV2-dependent responses in a primary culture of mouse endometrial stromal cells and attenuated cell proliferation and migration in in vitro cell proliferation and wound healing assays. Taken together, our study revealed that the antihistaminic drugs loratadine, astemizole and clemizole target TRPV2 in a concentration-dependent manner. The identification of these antihistaminic drugs as blockers of TRPV2 may form a new starting point for the synthesis of more potent and selective TRPV2 antagonists, which could further lead to the unravelling of the physiological role of the channel.
Topics: Animals; Astemizole; Benzimidazoles; Calcium; Calcium Channel Blockers; Calcium Channels; Cell Proliferation; HEK293 Cells; Histamine Antagonists; Humans; Loratadine; Mice; Stromal Cells; TRPV Cation Channels; Transient Receptor Potential Channels
PubMed: 35714693
DOI: 10.1016/j.ejphar.2022.175086 -
Current Organic Synthesis 2023Benzazoles (Bz) and derivatives are interesting molecules in medicinal chemistry. Several of these compounds display diverse biological activities; some are still used... (Review)
Review
Benzazoles (Bz) and derivatives are interesting molecules in medicinal chemistry. Several of these compounds display diverse biological activities; some are still used in clinical applications. In this way, synthetic chemists are interested in developing new procedures to access compounds with the guanidine moiety as 2-aminobenzimidazole (2ABI), Astemizole (antihistaminic), Albendazole (anthelmintic) and Carbendazim (fungicide). The guanidine group, considered a super base bonded to a benzoxazole ring, results in the 2-guanidinobenzazoles (2GBZs), which could modify the biological activity of these heterocycles. On these bases, we prepared this review article, which covers chemical aspects of 2-guanidinobenzoazoles as potential therapeutic agents and summarizes the current knowledge on the mechanism of pharmacological activities such as cytotoxic, inhibition of cell proliferation via angiogenesis and apoptosis. Specifically, it highlights the most recent results of synthetic approaches to 2GBZs with variety of modifications and functionalization with aromatic, carbohydrate, and amino-acid moieties as illustrated on 28 schemes and is concluded with 141 references. Additionally, the format of this interesting review is exclusively designed on specifically classified category of chemical reactions with primary precursors such as o-substituted anilines and 2-aminobenzazoles (2ABZs). This will constitute the important goals and novelty of this paper to facilitate synthetic chemists in the investigation about development of new pharmacophores.
Topics: Anti-Infective Agents; Antineoplastic Agents; Guanidine
PubMed: 35708075
DOI: 10.2174/1570179419666220615143529 -
Drug Metabolism and Disposition: the... Nov 2022Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically...
Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven genes contain nine coding exons and are located in corresponding genomic regions, with the pig genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in the small intestine with additional expression in the kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocityversus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. SIGNIFICANCE STATEMENT: Dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in the small intestine, similar to human CYP2J2.
Topics: Animals; Astemizole; Butyrophenones; Cats; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Dogs; Humans; Phylogeny; Piperidines; Swine; Terfenadine
PubMed: 35701183
DOI: 10.1124/dmd.122.000930