JAK1 represents a clinically validated target for inflammatory bowel disease (IBD), but the safety concerns associated with systemic JAK1 inhibition remain unaddressed. In this study, we designed and synthesized a series of 2,4-diaminopyrimidine derivatives as novel, gut-restricted, selective JAK1 inhibitors for the treatment of IBD to mitigate potential systemic side effects. Among them, compound 38 exhibited potent JAK1 inhibition (IC50 < 0.5 nM) and robust cellular potency (IC50 = 28 nM) in the JAK/STAT signaling pathway. It also demonstrated remarkable selectivity over JAK2 (>312-fold), JAK3 (>20,000-fold), and TYK2 (>354-fold), respectively. Furthermore, compound 38 displayed high intestinal exposure but low systemic exposure (<1 ng/mL) in mice, confirming its gut-restricted nature. In a DSS-induced colitis model, compound 38 significantly ameliorated inflammatory symptoms, promoted epithelial repair, and suppressed the production of proinflammatory cytokines (e.g., TNF-α and IL-6). Thus, compound 38 was identified as a therapeutically promising candidate compound for treating IBD.

The Nod-like receptor protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, governs the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 and thereby plays...

A novel industrial process for the synthesis of levalbuterol hydrochloride has been developed, involving five key chemical reactions integrated into four steps: alpha-bromination of the carbonyl group, nucleophilic substitution of the alpha-bromo carbonyl with an amine, ester hydrolysis, debenzylation, and asymmetric carbonyl reduction. The process affords levalbuterol hydrochloride in an overall yield of 43% with >99.8% enantiomeric excess (ee). Continuous-flow synthesis suppresses dibrominated impurities and improves operational safety. High selectivity for debenzylation and asymmetric reduction is achieved using a formic acid/triethylamine hydrogen-donor system in combination with appropriate catalysts. This process overcomes the limitations of poor stereoselectivity in conventional routes and provides a safe, high-quality, and cost-effective approach for the industrial production of levalbuterol hydrochloride.

This paper describes the development of a practical and chromatography-free route for the multigram-scale synthesis of plogosertib, a polo-like kinase 1 (PLK1) inhibitor. Compared with the synthetic route disclosed in Cyclacel’s patent, the present procedure employed an improved convergent strategy, in which pyrimido-diazepine intermediate and -configured aminobenzamide intermediate were prepared independently and then coupled via an acid-mediated nucleophilic aromatic substitution reaction. In the pyrimido-diazepine sequence, nitrile reduction was achieved using NaBH/CoCl·6HO under mild conditions, avoiding Raney Ni-catalyzed hydrogenation under pressurized hydrogen. Regioselectivity in the preparation of intermediate was improved by controlling the SAr reaction temperature. In the aminobenzamide sequence, the -isomeric impurity formed during reductive amination was effectively removed by MTBE slurry purification without column chromatography. The final acid-mediated SAr reaction also replaced the coupling-reagent-mediated amidation used in the reported process. Key transformations were systematically optimized with respect to reaction efficiency, selectivity, and operational practicality. The optimized process afforded plogosertib in 42.4% overall yield from compound with 99.9% HPLC purity, demonstrating its suitability for practical multigram-scale preparation.

A highly efficient cascade synthesis of various substituted 2-aminothiochromones was developed. The commercially available thiocarbonyldiimidazole (TCDI) acted as a key precursor in the construction of a sulfur-containing scaffold from 2-fluorophenyl ketone. Subsequent conjugated addition-elimination resulted in the corresponding 2-aminothiochromones under mild conditions. This simple protocol tolerates a broad range of functional groups and provides concise access to various 2-aminothiochromones in good to excellent yields (up to 94%).

This paper describes the development of an improved, practical, and scalable route for the multigram-scale synthesis of , a selective Nav1.7 inhibitor. The route was designed to avoid the carbon monoxide-mediated alkoxycarbonylation step used in the reported early development process and to provide practical access to both key fragments from readily available starting materials. The piperidine fragment was prepared through esterification, regioselective nucleophilic aromatic substitution, Suzuki coupling, and a one-pot deprotection/methyl esterification sequence. The chiral side-chain fragment was obtained from 1-(3,5-dichlorophenyl)ethanone by Corey–Bakshi–Shibata asymmetric reduction followed by mesylation. Key transformations, including Suzuki coupling, stereospecific -alkylation, and final amidation, were optimized to improve conversion, selectivity, and operational practicality. The developed process afforded in 23.5% overall yield with 99.71% purity by high-performance liquid chromatography. The structure of was confirmed by spectroscopic analysis, and selected intermediates were also characterized to support the reliability of the synthetic route.

Wee1 is a serine/threonine kinase that plays an important role in regulating DNA damage response and cell cycle checkpoints. Inhibition of Wee1 could abrogate cell cycle arrest, exacerbate DNA damage, and induce mitotic catastrophe and apoptosis. Herein, a novel series of 2-aminopyrimidine-5-carboxamide derivatives were designed, synthesized, and evaluated as Wee1 inhibitors. Among them, compound WC-27 exhibited excellent inhibitory activity against Wee1 (IC50 = 2.11 nM) and high selectivity over PLK1 (IC50 > 1000 nM), suggesting that it may reduce off-target effects on PLK1 and thereby potentially mitigate the myelosuppression associated with Wee1 inhibitors. Meanwhile, it displayed acceptable antiproliferative activity against NCI-H1299 cell line with an IC50 value of 1.05 μM. Further investigation showed that compound WC-27 could arrest NCI-H1299 cells in S phase and induce apoptosis in a dose-dependent manner. Moreover, compound WC-27 displayed moderate liver microsomal stability and an excellent pharmacokinetic profile (AUC0-t = 2370 ng·h·mL-1, oral bioavailability of 49.5%) in Sprague-Dawley rats, acceptable PPB, low risk of drug-drug interactions and no apparent toxicity was observed in the acute toxicity assay. Overall, these results indicate that compound WC-27 is a promising Wee1 inhibitor.

In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.

A traditional Chinese medicine (TCM) monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects, and has gained much attention for treating neuronal diseases. However, the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier (BBB). Exosomes are small extracellular vesicles (EVs) ranging in size from 30 to 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages, including low toxicity, low immunogenicity, high stability in blood, and the ability to cross the BBB. This review discusses the biogenesis, components, stability, surface modification, isolation technology, advantages, and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems. Furthermore, exosome-encapsulated TCM monomers exert neuroprotective roles, such as anti-inflammation, anti-apoptosis, anti-mitophagy, and anti-oxidation, in various neuronal diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia and reperfusion (CI/R) injury, as well as anti-drug resistance, anti-tumorigenesis, anti-angiogenesis, and promotion of apoptosis in brain tumors, providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.

Polo like kinase 1 (PLK1) is a serine/threonine kinase that plays an important role in multiple phases of the cell cycle, inhibiting its activity has been considered an effective treatment for acute myeloid leukemia (AML). Here, we reported a series of highly potent PLK1 inhibitors. Among them, compound WD6 was identified as the most promising PLK1 inhibitor, with an IC50 value of 0.27 nM and greatly reduced hERG affinity, with 12.78 % inhibition at 10 μM. Compound WD6 displayed significant anti-proliferative activities against MV4-11 (IC50 = 23.3 nM), excellent pharmacokinetic properties (t1/2 = 7.59 h, AUC0-t = 29300 ng h mL-1 and F = 35.1 %), good PPB and low risk of drug-drug interactions. In vivo, oral administration of compound WD6 at a dose of 20 mg/kg effectively suppressed the tumor growth in the MV4-11 xenograft mouse model. Further research indicated that WD6 exhibited excellent kinase selectivity, arresting MV4-11 cells at G2 phase, inducing apoptosis in a dose-dependent manner and down-regulating the transcription of the proliferation-related oncogene c-MYC. These results showed that compound WD6 has the potential to be a promising drug candidate for treating AML.

Cancer immunotherapy is an emerging anti-cancer strategy that enhances immune circulation by targeting the immune system. Among the various targets, HPK1, a member of the mammalian Ste20-like protein serine/threonine kinase family, serves as a crucial negative regulator of immune-mediated mechanisms, positioning it as a promising target for immunotherapy. Herein, based on the reported HPK1 inhibitors characterized by 2,4-diaminopyrimidine components, four series of derivatives were obtained through structural optimization methods. Compound 10c demonstrates significant inhibitory effects on HPK1 kinase, with an IC50 of 0.09 nM. Additionally, it markedly inhibits the phosphorylation of the downstream adaptor protein SLP76, with an IC50 of 33.74 nM, and effectively stimulates the secretion of the T cell activation marker IL-2, exhibiting an EC50 of 84.24 nM. These findings suggest that compound 10c holds considerable promise for applications in immunotherapy.

Polo-like kinase 1 (PLK1), the most well-studied kinase in the Polo like kinase (PLK) family, is a class of serine/threonine protein kinases that play a crucial role in cell cycle regulation, and is widely present in eukaryotes. PLK1 is considered a potential target for oncology drug development. We have synthesized and tested a novel acyl or sulfonyl groups-based derivative with dihydroindole as a potent inhibitor of PLK1. Among them, compound B7 exhibits good inhibitory activity against PLK1 with an IC50 value of 0.25 nM. At the same time, it showed significant antiproliferative activity against three tumor-derived cell lines (MDA-MB-231 IC50 = 72.5 nM, MDA-MB-361 IC50 = 316 nM, MV-411 IC50 = 32.1 nM). Further investigation showed that B7 could arrest MV4-11 cells in G2 phase and induce apoptosis in a dose-dependent manner. And B7 can be stable under simulated gastric acid environmental conditions, and acceptable CYP 450 inhibition. Moreover, B7 has excellent plasma protein binding rates in human, rat, and mouse. The pharmacokinetic profile of B7 in rats is also superior to that of BI 2536 (AUC0-t = 578 ng·h·mL-1 vs 283 ng·h·mL-1), and the bioavailability of B7 is 20.1 %, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). These results suggest that B7 is a promising PLK1 inhibitor.

In our previous study, oxazolidinone EJMC-8b demonstrated potent antibacterial activity and drug-likeness but was limited by MAO-A inhibition, high plasma protein binding, and inferior in vivo efficacy compared to linezolid. Herein, we report the discovery of a promising compound D13, which exhibited excellent antibacterial activity against S. aureus, MSSA, MRSA, LRSA, and LREFa with MIC values of <0.03, 0.125, 0.25, <0.03, and 1 μg/mL, respectively. Subsequently, D13 displayed significantly reduced MAO-A and MAO-B inhibition (IC50 = 51.3 and 47.0 μM, respectively) and superior PK profiles (F = 113.1%) in mice. Ultimately, compound D13 demonstrated potent and dose-dependent efficacy in vivo in a mouse model of LRSA peritonitis infection. However, compound D13 showed potential cytotoxicity and mitochondrial toxicity, although it does not have acute toxicity in mice. Through our comprehensive studies, compound D13 has emerged as a promising back-up compound for the treatment of linezolid-resistant bacterial infections and deserves further research.

The NADPH oxidase (NOX) 2-dependent reactive oxygen species (ROS) mediate cell autophagy to participate in a variety of cardiovascular diseases. However, whether NOX2-mediated ROS facilitates angiotensin II-induced cardiac hypertrophy by promoting cardiomyocyte autophagy is still unknown. Mouse cardiomyocytes were stimulated with angiotensin II for different time in the presence and absence of apocynin or 3-methyladenine. Angiotensin II-induced NOX2-knockdown cardiomyocytes and NOX2-deficient mice were used to explore the function of NOX2 in angiotensin II-induced cardiomyocyte hypertrophy, oxidative stress (OxS), and autophagy. The abundance of several proteins was detected by western blot. Wheat germ agglutinin and Masson's staining determined cardiomyocyte size and cardiac fibrosis. OxS was determined by analyzing ROS production, malondialdehyde levels, and superoxide dismutase activity. Co-immunoprecipitation was performed to explore the S-glutathionylation of autophagy-related gene 4B (Atg4B). Apocynin and 3-methyladenine treatment decreased angiotensin II-mediated elevation in atrial natriuretic peptide and LC3 II/LC3 I protein levels but not NOX2. NOX2 silencing impaired angiotensin II-induced cell hypertrophy, ROS production, and autophagy in cardiomyocytes. Consistently, NOX2-deficient mice exhibited improvements in cardiac dysregulation, hypertrophy, and fibrosis, coupled with reduced OxS and autophagy. NOX2 silencing decreased angiotensin II-induced upregulation of Atg4B. Moreover, Atg4B knockdown improved angiotensin II-induced cardiomyocyte hypertrophy and autophagy, whereas NOX2 overexpression did not work in Atg4B knockdown-cardiomyocytes. Mechanistically, angiotensin II-induced NOX2 facilitates the S-glutathionylation of Atg4B. NOX2-dependent ROS facilitates angiotensin II-induced cardiac hypertrophy via Atg4B S-glutathionylation modification, indicating that targeting the S-glutathionylation of Atg4B may be a potential adjunct therapeutic strategy for cardiac hypertrophy, complementary to existing standard treatments.

Myocardial infarction (MI) is the leading cause of mortality in cardiovascular diseases and continues to pose a substantial challenge in clinical management, despite the availability of guideline-directed medical therapy. The present study aimed to investigate the potential protective effects of the NADPH oxidase inhibitor (NI) GSK2795039 on cardiac remodeling following MI, and to elucidate the underlying mechanisms involved. We established the MI model by ligating the left anterior descending artery in mice. Additionally, we replicated this model in vitro by stimulating H9C2 cells with levarterenol (LN). The assessment of cardiac function, cardiomyocyte size, apoptosis, infarct size, and mitochondrial structure was conducted utilizing echocardiography, WGA staining, TUNEL assay, Masson's staining, and electron microscopy, respectively. The investigation of this mechanism utilized colorimetry, Western blotting, flow cytometry, and RT-PCR techniques. Compared to mice with MI or H9C2 cells stimulated by LN, NI treatment significantly improved cardiac dysfunction and hypertrophy. It also resulted in a reduction of cardiomyocyte size and apoptosis, decreased infarct size, alleviated mitochondrial structural damage, lowered levels of malondialdehyde and NOX2, diminished ROS production while inhibiting NOX activity, and enhanced the activities of T-SOD, GSH-PX, as well as mitochondrial complexes I-V. Additionally, it led to an increase in mitochondrial OCR, ATP levels and MMP. These findings indicate that GSK2795039 can mitigate oxidative stress and mitochondrial dysfunction through the inhibition of NOX2, thereby providing a cardioprotective effect against cardiac remodeling induced by MI. This suggests that GSK2795039 may possess therapeutic potential for patients following MI.

FGFR alterations, including fusions, amplifications, rearrangements, and mutations, exist as pathogenic drivers or bypass mechanisms in numerous diseases and cancers. Thus, FGFRs represent crucial therapeutic targets, particularly in oncology. Various agents, especially selective FGFR inhibitors, have shown promising therapeutic potential in oncological diseases. However, off-target toxicities (e.g., hyperphosphatemia) and acquired drug resistance associated with FGFR inhibitors often result in disease progression and unfavorable outcomes for patients, constraining clinical utility. This drives next-generation FGFR therapeutics development, particularly enhancing isoform selectivity and overcoming resistance mutations. This review summarizes FGFR protein architecture, biological functions, and disease associations, while highlighting advances (2020-present) in FGFR inhibitors and degraders, including design strategies, SARs, binding modes, and biological evaluation. Additionally, the unique mechanisms underlying subtype selectivity and resistance to drug-resistant mutations are discussed, providing strategic insights for developing improved FGFR-targeted agents.

This paper described the development of a practical, improved and efficient method for the multigram-scale synthesis of volasertib, an injectable bioavailable potent and selective inhibitor of PLK1. The key to this optimization was the design and development of a novel synthetic strategy, which involved the preparation of key intermediate 4-amino-N-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl-3-methoxybenzamide (W-5) through nitro reduction sequence and (7R)-2-chloro-7-ethyl-7,8-dihydro-8-(1-methylethyl)-6(5H)-pteridinone (W-11) through reductive cyclization and N-methylation reaction. The developed process provided 46

In order to detemine the anti-diabetic effect and potential mechanism of a novel soluble epoxide hydrolas inhibitor(A34)on diabetic mice.Type 1 diabetes mellitus(T1DM)mice were induced by streptozotocin(50 mg/(kg·d)for 5 days,ip.)and the hypoglycemic effect of A34 were evaluated by water and food intake,non-fasting and fasting blood glucose,glucose tolerance and plasma insulin level in diabetic mice after water administration.The underlying mechanism was explored via measuring the expression level of sEH in islets,the morphological change of islets and the concerntration of cytokines INF-γ and IL-4 in plasma.Compared with diabetic model group,the water and food intake(p<0.01,p<0.05),blood glucose(p<0.01),glucose tolerance(p<0.01)and plasma insulin level(p<0.05)were improved in A34 group.Additionally,A34 could protect pancreatic islet morphology,suppress sEH expression in islet(p<0.01),reduce the ratio of INF-γ to IL-4 in plasma(p<0.05).These results showed that A34 prevents hyperglycemia and β-cell dysfunction through regulating the dynamic balance of pro-inflammatory and anti-inflammatory cytokines in diabetic mice.

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 mu g/mL), MSSA (MIC = 0.125 mu g/mL), MRSA (MIC = 0.06 mu g/mL), LRSA (MIC = 0.125 mu g/mL) and LREFa (MIC = 0.5 mu g/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0_ t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4%) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.