Drug Development Research最新文献

{"title":"Correction to “Mesalamine in Treatment of Intestinal Inflammatory Diseases—Formulation-Driven Strategies for Targeted Colonic Therapy and Remission Maintenance”","authors":"","doi":"10.1002/ddr.70393","DOIUrl":"10.1002/ddr.70393","url":null,"abstract":"<p>Sahoo B, Patel J. “Mesalamine in Treatment of Intestinal Inflammatory Diseases-Formulation-Driven Strategies for Targeted Colonic Therapy and Remission Maintenance.” <i>Drug Dev Res.</i> 2026 Jun;87(4):e70321. doi: 10.1002/ddr.70321. PMID: 42163435.</p><p>Table 2, reads as follows:\u0000\u0000 </p><p>It should be corrected as follows:\u0000\u0000 </p><p><b>2. Page 7, section 5.1, third sentence</b></p><p>“Table 2 indicates the different oral formulations of mesalamine in clinical use. The representative brands are Asacol, Claversal, Mezavant, Pentasa, and Salofalk, which have variations in formulations like enteric-coated tablets, prolonged-release tablets, or tablets of granules or micro-pellets (Ko et al. 2019).” Was incorrect.</p><p>This should be corrected as</p><p>“Table 2 indicates some representative oral mesalamine formulations currently in clinical use. Representative brands include Asacol, Claversal, Mezavant, Pentasa, and Salofalk. These products differ in their delivery technologies, for example, enteric‑coated tablets, prolonged‑release granules, or micro‑pellet formulations (Ko et al., 2019; Dr. Falk Pharma GmbH, 2024; Shire Pharmaceuticals Ltd, 2024; Tillotts Pharma AG, 2024)”</p><p><b>3. Page 2</b></p><p>“Standard induction doses range from 2.4 to 4.8 g/day orally, with rectal doses of 4 g nightly for enemas or 1 g nightly for suppositories.” Was incorrect</p><p>This should be corrected as “Standard induction therapy with oral mesalamine generally involves doses of 2–3 g/day. Escalation to high-dose regimens (&gt; 3 g/day, typically up to 4.8 g/day) is reserved for patients with moderate disease activity or inadequate response to standard dosing. Rectal mesalamine remains an important adjunct, with enemas at 4 g nightly and suppositories at 1 g nightly for distal disease. This stratification between standard and high-dose induction is consistent with contemporary treatment recommendations, including the latest ECCO guidelines (Gisbert et al., 2026).”</p><p><b>ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment</b> Gisbert JP, Chaparro M, Verstockt B, et al. <i>Journal of Crohn's and Colitis</i>. 2026;20(7). DOI: 10.1093/ecco-jcc/jjag066</p><p>We apologize for this error.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70393","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bavachin Attenuates Cognitive Impairment in Scopolamine-Induced Amnesia: Behavioral, Biochemical and Molecular Insights","authors":"Md. Shadin,&nbsp;Monisha Brati Barua,&nbsp;Talat Ali,&nbsp;Farha Farahim,&nbsp;Md. Ripon,&nbsp;Mehedi Hasan Linkon,&nbsp;Md. Shakil,&nbsp;Mohammed Alfaifi,&nbsp;Faisal H. Altemani,&nbsp;Abdullah H. Altemani,&nbsp;Faisal Alsenani,&nbsp;Muhammad Torequl Islam","doi":"10.1002/ddr.70394","DOIUrl":"10.1002/ddr.70394","url":null,"abstract":"<div>\u0000 \u0000 <p>Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive-protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)-induced amnesia model. Male Swiss albino mice were pretreated with BVC (10–40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y-maze, and Morris water maze. BVC attenuated SCP-induced memory deficits in a dose-dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater-than-additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC₅₀ = 27.7 µM) and attenuates SCP-induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater-than-additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Evaluation of Gastrointestinal Factors Influencing the Stability and Function of mRNA-Encapsulated Lipid Nanoparticles","authors":"Toma Shinkai,&nbsp;Koki Ogawa,&nbsp;Mohamed S. Mohamed,&nbsp;Tetsuya Ozeki","doi":"10.1002/ddr.70392","DOIUrl":"10.1002/ddr.70392","url":null,"abstract":"<p>Owing to the intrinsic instability of mRNA, its routes of administration are limited, and to date, only injectable delivery has been clinically applied. In contrast, oral administration exposes mRNA to a variety of substances in the gastrointestinal (GI) tract. Despite these challenges, oral delivery remains the most familiar and convenient route for patients, making the development of orally administrable mRNA-encapsulated lipid nanoparticles (mRNA–LNPs) highly desirable. However, no studies have directly examined how mRNA–LNPs are affected within the GI environment. In the present study, we investigated the effects of representative GI components on mRNA–LNPs. Among several digestive enzymes, pepsin markedly reduced the protein-expression efficiency of the particles, whereas amylase had no effect. Pepsin-treated particles exhibited increased size, suggesting that structural alterations contributed to the observed functional loss. Lipase at high concentrations impaired nanoparticle function. Because lipase hydrolyzes ester bonds in lipids, we examined LNPs incorporating C12-200, an ionizable lipid lacking ester bonds, instead of SM-102. The C12-200 formulation showed reduced susceptibility to lipase-induced functional loss, indicating that enzymatic lipid degradation underlay the observed effects. Simulated gastric fluid also significantly diminished particle functionality. A detailed analysis of the relationship between functionality and pH revealed that impairment primarily occurred at approximately pH 1 but not at pH ≥ 3. Collectively, these findings identify the key GI factors that compromise mRNA–LNP integrity and provide important insights into the rational design of orally administrable mRNA–LNP formulations.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149024100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine-1-Phosphate Attenuates LPS-Induced Inflammatory Cardiac Injury in Association With RASGRP1–S100A9–NLRP3 Signaling","authors":"Chaofu Yue,&nbsp;Qiaolin Li,&nbsp;Chunyan Li,&nbsp;Taoxian Yang,&nbsp;Xian Huang,&nbsp;Feng Yue,&nbsp;Qiuyu Long,&nbsp;Rong Li,&nbsp;Rong Lei,&nbsp;Qingsong Ma,&nbsp;Caimei Hu,&nbsp;Qian Yang,&nbsp;Yongjun Yan,&nbsp;Yuan Liu,&nbsp;QinYong Yan,&nbsp;Mei Yang","doi":"10.1002/ddr.70391","DOIUrl":"10.1002/ddr.70391","url":null,"abstract":"&lt;p&gt;Lipopolysaccharide (LPS) induces endotoxemia-associated inflammatory cardiac injury rather than classical viral or autoimmune myocarditis. Sphingosine-1-phosphate (S1P) regulates cardiovascular and immune responses, predominantly through S1P receptors, but whether it also modulates macrophage-associated inflammatory signaling during LPS-induced cardiac injury remains incompletely understood. This study investigated the role of the RASGRP1–S100A9–NLRP3 signaling axis in the cardioprotective effects of S1P. Transcriptomic and single-cell RNA-sequencing analyses were used to identify inflammation-associated candidate genes and their cellular distribution. Male Sprague-Dawley rats received a single intraperitoneal injection of LPS (8 mg/kg) followed by S1P treatment for 6 weeks. Histopathology, echocardiography, serum cardiac-injury markers, oxidative-stress indices, inflammatory cytokines, Western blotting, and cellular metabolic-flux assays were evaluated. RAW264.7 macrophages were used for mechanistic cellular studies. RASGRP1 or NLRP3 overexpression and S100A9-R101Q mutation were used to assess functional contributions. Molecular docking and molecular-dynamics simulations were complemented by SPR, MST, CETSA, DARTS, and Co-IP assays to evaluate S1P–RASGRP1 target engagement and pathway-associated protein interactions. Bioinformatic analyses identified RASGRP1 as a macrophage-enriched, inflammation-associated hub gene. In LPS-treated rats, S1P reduced myocardial inflammatory injury and collagen deposition, improved ejection fraction and fractional shortening, and decreased cardiac-injury, oxidative-stress, and inflammatory markers. In RAW264.7 macrophages, S1P attenuated inflammatory and oxidative-stress responses, restored oxidative phosphorylation and glycolytic capacity, and reduced the abundance of RASGRP1, S100A9, NLRP3, and ASC. SPR and MST supported a concentration-dependent biophysical interaction between S1P and RASGRP1; CETSA and DARTS provided complementary target-stability evidence. The molecular-dynamics trajectory showed substantial rearrangement of S1P from the starting pose before reaching a plateau and therefore supports conformational sampling rather than preservation of the original docked pose. Co-IP supported protein associations within the proposed inflammatory network. RASGRP1 or NLRP3 overexpression attenuated several S1P-associated protective effects. The S100A9-R101Q mutation also weakened several S1P-associated protective responses. SPR indicated a lower apparent dissociation constant for R101Q than for WT S100A9 after model-specific fitting, which is consistent with stronger or more persistent NLRP3 binding rather than loss of the S100A9–NLRP3 interaction. S1P mitigates LPS-induced inflammatory cardiac injury in association with altered macrophage RASGRP1–S100A9–NLRP3 signaling. Biophysical and target-stability assays support direct engagement of RASGRP1 by S1P. However, these findings do not establish RASGRP1 as the","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Design and Anticancer Activities of Small-Molecule BRAF Inhibitors: A Medicinal Chemistry Perspective","authors":"Shuyu Jia,&nbsp;Jieman Lin,&nbsp;Janjun Wu,&nbsp;Hao Xu,&nbsp;Qingwei Zeng,&nbsp;Meipin Liu,&nbsp;Jiayi Shen","doi":"10.1002/ddr.70389","DOIUrl":"10.1002/ddr.70389","url":null,"abstract":"<div>\u0000 \u0000 <p>BRAF is a cytoplasmic serine-threonine protein kinase that plays a critical role in the MAPK signaling pathway. BRAF is the only member of the RAF family activated by mutation in human cancers. Many classes of B-Raf small molecule inhibitors have been identified. In this review, we will highlight typical BRAF inhibitors developed during these decades and provide a reference for the exploration of more potential BRAF inhibitors in the future.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statins as Repurposed Anticancer Agents: Regulated Cell Death, the Tumor Immune Microenvironment, and the Translational Evidence Gap","authors":"Xu Zhou,&nbsp;Yizhang Chen,&nbsp;Hanxiao Hua,&nbsp;Bo Shen,&nbsp;Shuai Liang,&nbsp;Dong Hua","doi":"10.1002/ddr.70388","DOIUrl":"10.1002/ddr.70388","url":null,"abstract":"<div>\u0000 \u0000 <p>Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and reduce flux through the mevalonate pathway, which supplies both cholesterol and the non-sterol isoprenoids required for prenylation of small GTPases. Because this pathway is frequently activated in cancer, statins have become one of the most intensively studied candidates for oncological drug repurposing. Preclinical work indicates that statins can lower the threshold for apoptosis, modulate autophagy in either a pro-death or a cytoprotective direction, induce pyroptosis, and sensitize cells to ferroptosis, while also acting on CD8⁺ T cells, macrophages, dendritic cells, and cancer-associated fibroblasts within the tumor microenvironment. Clinical evidence, however, remains discordant with the strength of these mechanistic claims: favorable observational associations are susceptible to immortal-time bias, healthy-user bias, and confounding by indication, and randomized trials have been largely neutral for tumor-directed endpoints. This narrative review appraises the mechanistic, preclinical, and clinical literature using an explicit five-tier evidence hierarchy, and treats two constraints as analytical tools rather than closing caveats: the pharmacological heterogeneity of individual statins, and the one-to-two order-of-magnitude gap between concentrations used in cancer-cell experiments and free drug concentrations achievable in patients. We conclude that statins are biologically plausible but clinically unproven anticancer agents whose evaluation should proceed through biomarker-selected, pharmacodynamically validated combination trials rather than unselected add-on designs.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Evaluation of Plumbagin and Sorafenib in NDEA–TAA-Induced Hepatocellular Carcinoma: Effects on Hepatic Function, Redox Homeostasis and Histopathology","authors":"Akinade K. Adetola,&nbsp;Regina N. Ugbaja,&nbsp;Olubisi E. Adeyi,&nbsp;Funmilola C. Thomas,&nbsp;Johnson A. Adeyemo,&nbsp;Oluwafemi A. Odesola","doi":"10.1002/ddr.70390","DOIUrl":"https://doi.org/10.1002/ddr.70390","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a major contributor to cancer-related mortality worldwide and is closely linked to oxidative stress and progressive hepatic dysfunction. This study investigated the effects of plumbagin on antioxidant defense systems and hepatic function markers in an N-nitrosodiethylamine–thioacetamide (NDEA-TAA)-induced experimental model of HCC and compared its efficacy with that of sorafenib. Male Wistar rats were assigned to five groups: normal control, plumbagin-only, HCC control, HCC treated with plumbagin, and HCC treated with sorafenib. Hepatocarcinogenesis was induced using NDEA-TAA, after which antioxidant parameters including reduced glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) were evaluated alongside hepatic function markers alanine aminotransferase (ALT) and albumin (ALB). The HCC control group exhibited significant reductions in GSH, GST, GPx, CAT, and SOD activities, accompanied by elevated MDA and ALT levels and decreased ALB concentrations (<i>p</i> ≤ 0.05), indicating severe oxidative stress and hepatic injury. Treatment with plumbagin significantly restored antioxidant enzyme activities, reduced lipid peroxidation, and improved hepatic function relative to the untreated HCC group. These effects were comparable to, and in certain parameters exceeded, those observed following sorafenib administration. The findings demonstrate that plumbagin possesses substantial antioxidative and hepatoprotective properties capable of mitigating oxidative damage and improving liver function in experimental HCC. These findings support further investigation of plumbagin as a redox-modulating candidate in HCC and a basis for future studies incorporating combination treatment, molecular validation and translational models.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gypenosides Damulin A and Damulin B Inhibit Hepatocellular Carcinoma by Regulating Cholesterol Synthesis","authors":"Fang-Fang Li,&nbsp;Can Cui,&nbsp;Zhou-Juan Zheng,&nbsp;Man-Yu Xiao,&nbsp;Si Li,&nbsp;Peng Xie,&nbsp;Xiang-Lan Piao","doi":"10.1002/ddr.70387","DOIUrl":"10.1002/ddr.70387","url":null,"abstract":"<div>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system. The liver is the primary organ for cholesterol production and metabolism in the body. Abnormal cholesterol levels can promote the initiation and progression of liver cancer, as well as influence treatment and patient prognosis. Damulin A and damulin B, a pair of isomeric dammarane-type saponins isolated from heat-treated <i>Gynostemma pentaphyllum</i>, have been shown to inhibit HCC cell proliferation and migration, arrest the cell cycle at the G0/G1 phase, induce apoptosis, and reduce intracellular cholesterol levels in vitro. Damulin B exhibited more potent effects in these assays. RNA sequencing and Western blot analysis revealed that both compounds downregulate the expression of key cholesterol biosynthesis-related genes, namely isopentenyl-diphosphate delta isomerase 1 (IDI1) and geranylgeranyl diphosphate synthase 1 (GGPS1). However, damulin A uniquely increased the expression of other cholesterol pathway genes: farnesyl diphosphate synthase (FDPS), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), and lanosterol synthase (LSS). These findings indicate that damulin A and damulin B regulate intracellular cholesterol biosynthesis through distinct mechanisms, which may account for their differential inhibitory effects on hepatocellular carcinoma.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Tetrahydro-β-Carboline-Based Spirocyclic Peptides via Cascade N-Boc Deprotection and Pictet-Spengler Reaction of Tryptophan: Potent Anti-Inflammatory and Anti-Oxidant Activities","authors":"Shravani Battula,&nbsp;Vaishnavi Kambhampati,&nbsp;Sai Balaji Andugulapati,&nbsp;Kiranmai Nayani","doi":"10.1002/ddr.70384","DOIUrl":"10.1002/ddr.70384","url":null,"abstract":"<div>\u0000 \u0000 <p>Inflammation is a tightly regulated response that maintains tissue homeostasis; however, its dysregulation in the lung contributes to acute lung injury (ALI), characterised by excessive cytokine production, oxidative stress, epithelial-endothelial barrier disruption, and impaired gas exchange. In the current study, we report the synthesis of 1,2,3,4-tetrahydro-β-carboline (THβC)-based spirocyclic peptides by an efficient cascade strategy involving <i>N</i>-Boc deprotection and Pictet-Spengler cyclization, which was developed for tryptophan-containing peptides using 9-fluorenone, enabling the synthesis of THβC peptides. The reaction proceeds under mild conditions [C₆F₅OH (pentafluorophenol) catalyst, HFIP (1,1,1,3,3,3-Hexafluoro-2-propanol) solvent] to generate a novel spiro-β-carboline scaffold, with broad substrate scope across aromatic, aliphatic, and alicyclic ketones. Further, the anti-inflammatory potential of THβC derivatives was evaluated in LPS-stimulated macrophages and lung epithelial cells. Initial screening demonstrated that compounds <b>3a, 3aa, 3c</b>,<b>3e</b>, and <b>3 g</b> (20 μM) significantly reduced <i>Il-1β</i> levels compared with the LPS control. Subsequent structure–activity relationship studies identified compounds <b>3aa</b> and <b>3ag</b> as potent inhibitors of <i>Il-1β</i> expression, while compounds <b>3aa, 3ad, 3af</b> and <b>3ag</b> effectively suppressed <i>Ccl-2</i> and <i>Cox-2</i> expression. Based on their ability to attenuate intracellular ROS levels, compounds <b>3aa</b> and <b>3ag</b> were selected for further dose-response evaluation and assessment in lung epithelial cells. These compounds significantly downregulated key inflammatory mediators in both macrophages and epithelial cells. Immunocytochemical analyses further revealed that compounds <b>3aa</b> and <b>3ag</b> reduced LPS-induced VCAM expression and restored caveolin levels, indicating improved barrier integrity. Collectively, compounds <b>3aa</b> and <b>3ag</b> attenuate LPS-induced inflammation and oxidative stress while preserving epithelial barrier integrity, supporting their potential as leads for pulmonary inflammatory disorders.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in N- and S-Heterocycles as c-Jun-N-Terminal Kinase 3 Inhibitors for Alzheimer's Disease Treatment","authors":"Parul Yadav,&nbsp;Deepak Mishra,&nbsp;Ram Singh","doi":"10.1002/ddr.70381","DOIUrl":"10.1002/ddr.70381","url":null,"abstract":"<div>\u0000 \u0000 <p>c-Jun-N-terminal kinase 3 (JNK3) inhibitors are emerging as promising therapeutic agents for the treatment of Alzheimer's disease (AD). Predominantly expressed in the central nervous system (CNS), JNK3 plays a crucial role in neuronal apoptosis and inflammation, processes that are often dysregulated in neurodegenerative conditions. In recent years, a diverse range of heterocycle scaffolds has been explored as selective JNK3 inhibitors, demonstrating significant potential in modulating disease pathology. Structure–activity relationship (SAR) studies have further facilitated the rational design and optimization of these compounds, improving their potency, selectivity, and pharmacokinetic profiles. By selectively inhibiting JNK3, these small compounds can mitigate neuroinflammation and promote neuronal survival. The development of small molecule JNK3 inhibitors offers a targeted approach that may minimize side effects. This article explores various heterocyclic molecules such as pyrazoles, thiazoles, imidazoles, and thiophenes, evaluated for JNK3 inhibition. This review will help medicinal chemists to design and develop new molecules based on established data on isoform-selective JNK3 inhibitors.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 7","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}