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Scientific Reports Jun 2024Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR... (Comparative Study)
Comparative Study
Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR T790M-positive non-small-cell lung cancer. We evaluated the effectiveness of lazertinib compared with osimertinib using an external control. We obtained individual patient data for the lazertinib arm from the LASER201 trial and the osimertinib arm from registry data at the Samsung Medical Center. In total, 75 and 110 patients were included in the lazertinib and osimertinib groups, respectively. After propensity score matching, each group had 60 patients and all baseline characteristics were balanced. The median follow-up duration was 22.0 and 29.6 months in the lazertinib and osimertinib group, respectively. The objective response rate (ORR) were 76.7% and 86.7% for lazertinib and osimertinib, respectively (p = 0.08). The median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI] 9.5-19.1) and 14.4 months (95% CI 11.8-18.1) for the lazertinib and osimertinib group, respectively (hazard ratio [HR] 0.97; 95% CI 0.64-1.45, p = 0.86). The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25-0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Male; Female; Lung Neoplasms; Aged; Middle Aged; Acrylamides; Aniline Compounds; Protein Kinase Inhibitors; Aged, 80 and over; Treatment Outcome; Progression-Free Survival; Mutation; Adult; Pyrimidines; Indoles; Morpholines; Pyrazoles
PubMed: 38918528
DOI: 10.1038/s41598-024-65220-z -
Reumatismo Jun 2024The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory...
The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.
Topics: Humans; Arthritis, Rheumatoid; Female; Purines; Aged; Azetidines; Pyrazoles; Sulfonamides; Creatine Kinase; Myalgia; Antirheumatic Agents; Janus Kinase Inhibitors
PubMed: 38916168
DOI: 10.4081/reumatismo.2024.1620 -
BioRxiv : the Preprint Server For... Jun 2024Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034...
Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 ( ) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog exhibited a / ratio >10,000 M s . 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like . The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.
PubMed: 38915519
DOI: 10.1101/2024.06.12.598722 -
Journal of Medicinal Chemistry Jun 2024A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned...
A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce and , exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8 T-cells, and helper CD4 T-cells in the spleen. These findings underscored the bifunctional capabilities of () with excellent oral bioavailability ( = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.
PubMed: 38913493
DOI: 10.1021/acs.jmedchem.4c00400 -
Organic & Biomolecular Chemistry Jun 2024Thiopyrans and their fused derivatives have significant synthetic relevance owing to their biological importance and occurrence in natural products. The current article... (Review)
Review
Thiopyrans and their fused derivatives have significant synthetic relevance owing to their biological importance and occurrence in natural products. The current article provides an overview of synthetic strategies employed for the construction of thiopyran-fused heterocycles. In particular, this article discusses synthetic methods for the fusion of thiopyran with heterocycles such as indole, quinoline, pyrimidine, pyridine, thiophene, chromene, oxazole, pyrazole, pyran and furan and covers the literature from 2013 to 2024. The most common precursors for thiopyrano[2,3-]indoles, thiopyranoquinolines and thiopyranothiazoles are indoline-2-thione, 2-mercaptoquinoline-3-carbaldehyde and thiazolidinone, respectively, and various reactions involving these are described in detail here. Asymmetric syntheses of thiopyranoindoles achieved using chiral catalysts based on thiourea, proline and metal complexes are also included. The biological activity associated with some compounds is also discussed.
PubMed: 38912843
DOI: 10.1039/d4ob00497c -
Inorganic Chemistry Jun 2024Two Mn(II)-bridged Silverton-type {UMoO}-based polyoxomolybdates with different three-dimensional structures, Na(HO)[Mn(UMoO)] () and (NH)[KNa(μ-O)(HO)Mn(UMoO)]·4.6HO...
Two Mn(II)-bridged Silverton-type {UMoO}-based polyoxomolybdates with different three-dimensional structures, Na(HO)[Mn(UMoO)] () and (NH)[KNa(μ-O)(HO)Mn(UMoO)]·4.6HO (), were hydrothermally synthesized and further characterized, demonstrating a feasible strategy for the assembly of Silverton-type polyoxomolybdates. Additionally, is demonstrated to be a good heterogeneous catalyst in the condensation cyclization reaction of hydrazines and 1,3-diketones, and a range of valuable pyrazoles were produced in up to 99% yield.
PubMed: 38912662
DOI: 10.1021/acs.inorgchem.4c01055 -
Future Medicinal Chemistry 2024The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a...
The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. 20 new benzothiazole-appended indenopyrazoles, , were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Among all the hydroxypyrazolones, and showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Compounds and have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.
Topics: alpha-Glucosidases; Benzothiazoles; alpha-Amylases; Molecular Docking Simulation; Glycoside Hydrolase Inhibitors; Hypoglycemic Agents; Humans; Pyrazoles; Structure-Activity Relationship; Molecular Structure; Enzyme Inhibitors
PubMed: 38910576
DOI: 10.4155/fmc-2023-0384 -
Journal of Zhejiang University.... Jun 2024: Following the short-term outbreak of coronavirus disease 2019 (COVID-19) in December 2022 in China, clinical data on kidney transplant recipients (KTRs) with COVID-19...
: Following the short-term outbreak of coronavirus disease 2019 (COVID-19) in December 2022 in China, clinical data on kidney transplant recipients (KTRs) with COVID-19 are lacking. : We conducted a single-center retrospective study to describe the clinical features, complications, and mortality rates of hospitalized KTRs infected with COVID-19 between Dec. 16, 2022 and Jan. 31, 2023. The patients were followed up until Mar. 31, 2023. : A total of 324 KTRs with COVID-19 were included. The median age was 49 years. The median time between the onset of symptoms and admission was 13 d. Molnupiravir, azvudine, and nirmatrelvir/ritonavir were administered to 67 (20.7%), 11 (3.4%), and 148 (45.7%) patients, respectively. Twenty-nine (9.0%) patients were treated with more than one antiviral agent. Forty-eight (14.8%) patients were treated with tocilizumab and 53 (16.4%) patients received baricitinib therapy. The acute kidney injury (AKI) occurred in 81 (25.0%) patients and 39 (12.0%) patients were admitted to intensive care units. Fungal infections were observed in 55 (17.0%) patients. Fifty (15.4%) patients lost their graft. The 28-d mortality rate of patients was 9.0% and 42 (13.0%) patients died by the end of follow-up. Multivariate Cox regression analysis identified that cerebrovascular disease, AKI incidence, interleukin (IL)-6 level of >6.8 pg/mL, daily dose of corticosteroids of >50 mg, and fungal infection were all associated with an increased risk of death for hospitalized patients. : Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality. The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival, while higher doses of corticosteroids may increase the death risk.
Topics: Humans; Kidney Transplantation; Middle Aged; Male; Female; COVID-19; Retrospective Studies; China; Antiviral Agents; Adult; SARS-CoV-2; Hospitalization; Transplant Recipients; Aged; COVID-19 Drug Treatment; Antibodies, Monoclonal, Humanized; Azetidines; Purines; Pyrazoles; Sulfonamides
PubMed: 38910497
DOI: 10.1631/jzus.B2300538 -
Environmental Pollution (Barking, Essex... Jun 2024Pyraclonil is a new type of pyrazole herbicide, whose photochemical fate in aqueous solution has not been reported yet. In this study, effects on the photolysis rate...
Pyraclonil is a new type of pyrazole herbicide, whose photochemical fate in aqueous solution has not been reported yet. In this study, effects on the photolysis rate such as light source, pH, NO, Fe, fulvic acid (FA) and riboflavin (RF) were investigated. Pyraclonil photodegraded in pure water under both UV and simulated sunlight with half-lives of 32.29 min and 42.52 h, respectively. Under UV, the degradation rate of pyraclonil in pH 4 solution (0.0299 ± 0.0033 min) was about twice higher than that in pH 9 (0.0160 ± 0.0063 min). Under simulated sunlight, low concentration (0.1-1 mg/L) of FA, NO, Fe and RF noticeably promoted the photodegradation of pyraclonil. Then, with the combination of experimental UPLC-Q-TOF/MS and computational calculation of density functional theory (DFT), fourteen transformation products (TPs) of pyraclonil were identified with possible mechanism of C-N bond cleavage, photorearrangement, demethylation, hydroxylation and oxidation. Additionally, acute toxicity assessment was conducted through ECOSAR prediction and laboratory bioassays. The prediction results indicated that toxicity of TP157 to daphnid and green algae was 1.3 and 1.4 times higher than that of the parent, respectively. The bioassay results indicated that toxicities of TP157 and TP263 to C. vulgaris were about 1.6 and 5.9 times higher than that of the parent, respectively. The results provided a reference for elucidating the potential hazards of pyraclonil to non-target organisms and promoting its rational use.
PubMed: 38906402
DOI: 10.1016/j.envpol.2024.124381 -
PloS One 2024This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA.
METHODS
The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444.
RESULTS
Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings.
CONCLUSION
Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
Topics: Humans; Arthritis, Rheumatoid; Janus Kinase Inhibitors; Bayes Theorem; Pyrimidines; Piperidines; Network Meta-Analysis; Azetidines; Purines; Pyrroles; Pyrazoles; Sulfonamides; Randomized Controlled Trials as Topic; Treatment Outcome; Heterocyclic Compounds, 2-Ring; Niacinamide; Benzamides; Heterocyclic Compounds, 3-Ring; Antirheumatic Agents; Triazoles; Adamantane; Pyridines; Valine
PubMed: 38905267
DOI: 10.1371/journal.pone.0305621