Archiv der Pharmazie最新文献

Cediranib (AZD2171; CDB) is an oral pan-VEGF receptor tyrosine kinase inhibitor and a potent antiangiogenic agent. This study sought to develop a precise, rapid, dependable, and sustainable UPLC-MS/MS approach for measuring CDB in the human liver microsome (HLM) matrix, utilized for assessing the CDB metabolic stability inside this matrix. The validation processes for the UPLC-MS/MS system adhered to US-FDA rules for bioanalytical technique validation. The validated method utilized the HLM matrix throughout a level range of 1–4000 ng/mL with a duration of 1 min on UPLC-MS/MS instrumentation. The precision (%RSD) and accuracy (%E) rates for intraday and interday measurements varied from −1.41% to 8.0% and from −2.75% to 9.67%, respectively. The StarDrop software employed P450 and DEREK modules to evaluate metabolic lability and to characterize CDB structural warnings, respectively. The in vitro t_1/2 was determined to be 25.48 min, and the CDB intrinsic clearance was determined to be 31.82 mL/min/kg. In silico assessments indicate that slight structural modifications to the pyrrolidine moiety (61%), methyl group (32%), and the propyl group (7%) in drug design could increase the CDB metabolic stability. The assessment of in silico CDB ADME characteristics and metabolic stability is fundamental for progressing innovative drug research focused on augmenting metabolic stability.

Carbonic anhydrases (CAs) belong to a set of metalloenzymes that facilitate the reversible catalytic hydration of CO₂, playing crucial roles in pH regulation, respiration, and electrolyte secretion. Dysregulation of specific CA isoforms, particularly the human variants hCA I, II, IX, and XII, is implicated in multiple pathological conditions, including glaucoma, epilepsy, obesity, and various cancers. Traditionally, sulfonamide-based inhibitors have dominated the therapeutic landscape; however, their limitations, such as off-target side effects, poor selectivity for different isoforms, and allergic reactions, have galvanized interest in alternative scaffolds. This comprehensive review critically examines the burgeoning class of non-sulfonamide inhibitors targeting hCA isoforms, focusing on the chemical diversity, binding mechanisms, and structure–activity relationships of recently developed phenols, carboxylic acids, coumarins, dithiocarbamates, and polyamines. Special attention is given to the advances in X-ray crystallography and computational modeling that have illuminated binding modes distinct from classical sulfonamide interactions. By synthesizing the latest findings, this review aims to guide future efforts in the rational design of selective and efficacious non-sulfonamide CA inhibitors for clinical application.

The thiazolidinedione (TZD) scaffold has long been recognized for its pharmacological versatility, particularly in the treatment of metabolic and inflammatory disorders. Among its derivatives, 2,4-thiazolidinediones (2,4-TZDs) have emerged as a prominent class of antidiabetic agents with diverse molecular targets. While their role as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists is well established, recent studies have revealed additional therapeutic mechanisms, including inhibition of protein tyrosine phosphatase 1B (PTP-1B), α-amylase, α-glucosidase, and aldose reductase—each contributing to improved glucose regulation and diabetes management. Moreover, the rise of dual and multitarget inhibitors highlights the evolving therapeutic potential of 2,4-TZDs beyond conventional pathways. This review presents a comprehensive analysis of recent developments (2020–2025) in the medicinal chemistry, structure–activity relationships (SARs), and antidiabetic mechanisms of 2,4-TZDs. Key structural modifications and their influence on biological activity are critically evaluated, alongside updates on recent patent disclosures and ongoing clinical trials. By integrating medicinal chemistry insights with pharmacological data, this review aims to support the rational design of next-generation 2,4-TZD-based antidiabetic therapeutics.

This study presents a novel analytical and formulation strategy to enhance the oral delivery and quality assessment of Nirmatrelvir, a poorly water-soluble antiviral agent. A self-emulsifying drug delivery system (SEDDS) was developed using Labrafac MC 60, ethanol, and Transcutol HP (55:25:20), resulting in a nanoemulsion with a droplet size of 145.23 ± 3.23 nm, low polydispersity index (0.189 ± 0.023), and high transmittance (98.97 ± 0.25%). The formulation exhibited rapid emulsification (< 90 s) and significantly improved permeability, achieving a fivefold increase (Papp: 4.20 × 10⁻⁶ cm/s) across Caco-2 cell monolayers compared to the tablet formulation. A stability-indicating reverse-phase HPLC method was developed using a mobile phase of 5 mM potassium dihydrogen phosphate buffer (pH 4.0) and acetonitrile (40:60, v/v), and validated per ICH Q2(R1) guidelines. The method showed excellent linearity (R² = 0.9999), accuracy (98.6%–100.2%), precision (%RSD < 0.3%), and robustness. An optimized sample preparation protocol ensured efficient extraction of Nirmatrelvir from the SEDDS matrix with minimal interference. Forced degradation studies under ICH Q1A(R2) demonstrated that Nirmatrelvir remained stable under oxidative (98.44%), thermal (98.45%), and photolytic (98.50%) conditions. Maximum degradation was observed under alkaline stress (20.56% at 0.5 N NaOH), followed by acidic stress (13.53% at 5 N HCl). The major alkaline degradant (Rt 2.7 min) was characterized by LC-TQ/MS (m/z 518.2 [M+H]⁺). The method's sustainability was supported by an AGREE score of 0.64 and a Whiteness score of 85.4, offering a validated platform for routine analysis of Nirmatrelvir in lipid-based formulations.

The current research investigates a new therapeutic strategy for the management of knee osteoarthritis (KOA). For this purpose, we developed mixed polymeric micelles (MPM) encapsulating a natural phytotherapeutic drug, vanillic acid (VA), for intra-articular (IA) delivery. The developed systems were characterized by their particle size profile, zeta potential, morphology, physical stability, and in vitro drug release. Cremophor was found to be an essential component for the production of MPM with optimum particle size profile, as well as maintaining an F127/Cremophor/TPGS weight ratio of 3:2:1. Coating the optimized formulation with hyaluronic acid (HA) provided a dual benefit of sustaining VA release and providing synergistic anti-osteoarthritic activity in an monosodiumiodoacetate-induced KOA model in rats. The proposed HA-coated MPM system encapsulating VA provides a promising strategy for the inhibition of KOA progression.

Carbazoles are an important class of aromatic compounds having numerous applications in pharmaceuticals, including anticancer, anti-inflammatory, and antibacterial activity. Traditional synthesis methods, while successful, frequently use toxic chemicals, hazardous solvents, and energy-intensive procedures, raising serious environmental problems. This study discusses current advances in green carbazole synthetic approaches, with a focus on environmentally friendly strategies such as microwave-assisted reactions, photoredox catalysis, and the use of recyclable metal catalysts such as gold and palladium. Sustainable techniques, such as solvent-free processes, aqueous systems, and renewable resources, are explored alongside mechanistic insights into improving atom economy and reducing waste. These changes, which incorporate green chemistry concepts, not only increase the sustainability of carbazole synthesis but also expand its therapeutic potential, paving the way for environmentally friendly advances in medicinal chemistry.

Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound 19 exhibited potent ATX inhibition (IC₅₀ = 4.2 nM) and significantly reduced lipophilicity (cLogP = 2.992) compared with PAT-409 (IC₅₀ = 4.9 nM, cLogP = 7.647). Molecular dynamics simulations indicated that 19 bound to the ATX protein in a highly stable manner. Furthermore, predictive analyses of drug-like properties and toxicity uncovered that 19 demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy.

l-Ascorbic acid exhibits paradoxical behavior as both antioxidant and pro-oxidant in cancer treatment, with mechanisms and optimal dosing remaining unclear. This in vitro study investigated l-ascorbic acid's effects on healthy lymphocytes and HL-60 leukemia cells using concentrations of 0.5–2 mg/mL for 6 and 24 h. Analyses included cell viability, gene expression, DNA damage, mutagenicity, and oxidative stress markers. The results demonstrated a dose-dependent increase in the metabolic activity of HL-60 cells, with a ~ sixfold increase observed at 2 mg/mL (p ≤ 0.001), and opposing modulation of FAS/catalase gene expression between the two cell types. In healthy lymphocytes, both genes were suppressed with increasing exposure, while HL-60 cells exhibited significant early induction (29-fold for FAS and 47-fold for catalase, p ≤ 0.001). l-Ascorbic acid concentrations (0.5–2 mg/mL) exhibited no significant genotoxicity in healthy cells, increased antioxidant status in healthy lymphocytes, and elevated oxidative stress (a 1.4-fold increase in the oxidative stress index at 24 h, p ≤ 0.001) in HL-60 cells. Ames testing confirmed non-mutagenicity, while plasmid analysis revealed bimodal effects, being pro-oxidant at an intermediate dose and protective at a high dose. These findings suggest that l-ascorbic acid requires cell-type-specific application in hematological malignancies and may offer a therapeutic window in leukemia treatment protocols, providing a foundation for optimizing combination strategies with conventional chemotherapeutics.