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The New England Journal of Medicine Jul 2023
Topics: Humans; Acetamides; Antineoplastic Agents; Carcinoma, Squamous Cell; Pyrazoles; Skin Neoplasms; Protein Kinase Inhibitors
PubMed: 37437151
DOI: 10.1056/NEJMc2304157 -
European Journal of Medicinal Chemistry Dec 2023This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide...
This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e, its bioisosteric carboxylic acid as in compounds 5a-e and 8e, ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7, hydrazide derivative 10e, hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b, 5b, 5d, 5e, 6b, 9b, 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e, 9d, 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 μM), renal cancer cell line (786-0; TGI = 4.32 μM) and breast cancer cell line (HS 578 T; TGI = 5.43 μM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI (0.45, 0.89 and 1.18 μM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786-0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis.
Topics: Humans; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Molecular Docking Simulation; Structure-Activity Relationship; Acetazolamide; Carbonic Anhydrase IX; Protein Isoforms; Pyrazoles; Molecular Structure; Benzenesulfonamides
PubMed: 37748386
DOI: 10.1016/j.ejmech.2023.115805 -
The Medical Letter on Drugs and... May 2024
Topics: Humans; Quinoxalines; Pyrazoles; Antineoplastic Agents; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Protein Kinase Inhibitors; Urologic Neoplasms; Treatment Outcome
PubMed: 38696316
DOI: 10.58347/tml.2024.1702g -
International Journal of Molecular... May 2024In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged...
In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1-pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2-binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 μM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.
Topics: Humans; Pyrazoles; Antineoplastic Agents; Cell Proliferation; Cell Movement; Cell Line, Tumor; Urea
PubMed: 38791418
DOI: 10.3390/ijms25105380 -
International Journal of Dermatology Jun 2024
Review
Topics: Humans; Janus Kinase Inhibitors; Alopecia; Cicatrix; Pyrazoles; Pyrimidines; Nitriles; Sulfonamides; Treatment Outcome; Azetidines; Heterocyclic Compounds, 3-Ring; Piperidines; Purines
PubMed: 38571280
DOI: 10.1111/ijd.17153 -
Structure (London, England : 1993) Dec 20234-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine...
4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.
Topics: Humans; Tyrosinemias; Thiadiazoles; Pyrazoles; Enzyme Inhibitors; Herbicides
PubMed: 37794595
DOI: 10.1016/j.str.2023.09.005 -
The Lancet. Haematology Mar 2024Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who...
BACKGROUND
Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG.
METHODS
SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 μg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed.
FINDINGS
54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment.
INTERPRETATION
Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated.
FUNDING
Novartis Pharmaceuticals.
Topics: Adult; Female; Humans; Male; Anemia, Aplastic; Antilymphocyte Serum; Benzoates; Cyclosporine; Hydrazines; Pyrazoles; Drug Therapy, Combination
PubMed: 38335978
DOI: 10.1016/S2352-3026(23)00395-2 -
Journal of Drugs in Dermatology : JDD Mar 2024Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been...
Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been established in atopic dermatitis and vitiligo, recent reports suggest its potential efficacy in treating other dermatoses. Specifically, topical ruxolitinib may be an effective treatment option for refractory dermatological conditions that are inflammation-driven with dysregulated activity of cytokines implicated in the JAK/STAT pathway. In this case series, we present four novel clinical applications of topical ruxolitinib in treatment-resistant dermatological conditions. These cases include pediatric lichen sclerosus et atrophicus, morphea, perioral dermatitis, and notalgia paresthetica. All four patients reported noticeable symptomatic improvement and a significant improvement in the condition of their skin lesions. Our results suggest that ruxolitinib cream can successfully manage these conditions and may serve as supporting evidence for its formal evaluation. J Drugs Dermatol. 2024;23(3): doi:10.36849/JDD.7696.
Topics: Humans; Child; Janus Kinases; STAT Transcription Factors; Signal Transduction; Cytokines; Janus Kinase Inhibitors; Nitriles; Pyrazoles; Pyrimidines
PubMed: 38443119
DOI: 10.36849/jdd.7696 -
Brazilian Journal of Microbiology :... Dec 2023To find novel antibiotic drugs, six 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H derivatives named 1b, 1d (pyrazoles), 2a, 2b, 2c, and 2d (thiazoles) were evaluated in...
To find novel antibiotic drugs, six 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H derivatives named 1b, 1d (pyrazoles), 2a, 2b, 2c, and 2d (thiazoles) were evaluated in silico and in vitro. The in silico analyses were based on ADME pharmacokinetic parameters (absorption, distribution, metabolism, and excretion). The in vitro antibacterial activity was evaluated in Gram-positive and Gram-negative species (Staphylococcus aureus ATCC® 25904, Staphylococcus epidermidis ATCC® 35984, Klebsiella pneumoniae ATCC® 700603, and Acinetobacter baumannii ATCC® 19606), by determination of minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), kinetics curve, and antibiofilm assays. As results, the azoles have activity against the Gram-negative species K. pneumoniae ATCC® 700603 and A. baumannii ATCC® 19606. No antibacterial activity was observed for the Gram-positive bacteria evaluated. Thus, the azoles were evaluated against clinical isolates of K. pneumoniae carbapenemase (KPC) and A. baumannii multidrug-resistant (Ab-MDR). All azoles have antibacterial activity against Ab-MDR isolates (Gram-negative) with MIC values between 512 μg/mL and 1,024 μg/mL. Against KPC isolates the azoles 1b, 1d, and 2d present antibacterial activity (MIC = 1,024 μg/mL). In the kinetics curve assay, the 1b and 1d pyrazoles reduced significantly viable cells of Ab-MDR isolates and additionally inhibited 86.6 to 95.8% of the biofilm formation. The in silico results indicate high possibility to permeate the blood-brain barrier (2b) and was predict human gastrointestinal absorption (all evaluated azoles). Considering that the research and development of new antibiotics is a priority for drug-resistant pathogens, our study revealed the antibacterial and antibiofilm activity of novel azoles against K. pneumoniae and A. baumannii pathogens.
Topics: Humans; Thiazoles; Anti-Bacterial Agents; Microbial Sensitivity Tests; Pyrazoles; Biofilms
PubMed: 37656404
DOI: 10.1007/s42770-023-01110-2 -
Hematological Oncology Jul 2024Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR)... (Review)
Review
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Pyrazoles; Pyrimidines; Protein Kinase Inhibitors; Piperidines; Lymphoma, B-Cell; Tyrosine Kinase Inhibitors
PubMed: 38847437
DOI: 10.1002/hon.3294