Zyflo (zileuton) / Chiesi - LARVOL DELTA

Tailored [1,2,4]triazolo[1,5-a]pyrimidine hybrids as promising anti-inflammatory agents with COX/5-LOX/ROS/IL-6 multifunctional inhibitory activity: design, synthesis, SAR, and in silico study. (PubMed, RSC Adv) - "The most potent COX-2 inhibitor 6d exhibited reasonable 5-LOX inhibitory activity (IC50 = 1.031 µM) in comparison to the selective 5-LOX inhibitor zileuton (IC50 = 0.386 µM). Moreover, 6d exhibited potent inhibitory activity against the proinflammatory cytokine IL-6 (90.9% inhibition) and ROS scavenging activity (IC50 = 34.45 µM), exceeding the two references, celecoxib and diclofenac sodium...Ultimately, docking simulations and drug-likeness studies provided insights into the potential binding scenarios within the active sites of COX-2 and 5-LOX, while also predicting the oral bioavailability and toxicity of the newly synthesized compounds. Based on these findings, the designed scaffolds can be considered as promising multitargeted anti-inflammatory candidates worthy of further exploration."

Journal • IL6 • TNFA

Zileuton protects pancreatic stellate cells from oxidative stress and ferroptosis by modulating the Nrf2 pathway and mitochondrial activity. (PubMed, J Physiol Biochem) - "Finally, a drop in the reduction of resazurin by mitochondria and a slowing of the Krebs cycle flow rate were observed, whereas no detectable changes in mitochondrial membrane potential were noted in the presence of zileuton. We conclude that the inhibition of 5-LOX by zileuton places cells in a state of antioxidant readiness coupled with a protected metabolic deceleration."

Journal • Fibrosis • Oncology • Pancreatic Cancer • Solid Tumor • CAT • HMOX1

Comparative adjuvant therapy to reduce vancomycin-associated nephrotoxicity in an animal model. (PubMed, Antimicrob Agents Chemother) - "Montelukast only had a marginal effect in vancomycin-treated animals, whereas zileuton significantly delayed nephrotoxicity onset. These findings support further formulation and dose-optimization studies to repurpose zileuton as a renal-protective adjuvant."

Journal • Preclinical • Acute Kidney Injury • Infectious Disease • Nephrology • Renal Disease

Design, synthesis, and biological evaluation of novel pyrimidine-sulfonamide derivatives as multi-targeted COX-2/5-LOX/sEH inhibitors with potential antiproliferative properties. (PubMed, RSC Adv) - "Compound 4c demonstrated significant inhibition of COX-2 (IC50 = 0.11 ± 0.01 µM) and 5-LOX (IC50 = 0.46 ± 0.02 µM) with comparable efficacy to celecoxib (IC50 = 0.08 ± 0.0004 µM) and surpassing the standard Zileuton (IC50 = 0.69 ± 0.03 µM). Their efficacy against these two cell lines exceeded that of the reference compounds celecoxib, sorafenib, and doxorubicin. Docking analysis of compound 4c showed a good fit within the active sites of both COX-2 and human sEH."

Journal • Breast Cancer • Oncology • Pancreatic Cancer

Computational and artificial intelligence-guided discovery of potential therapeutic candidates targeting Ml0099 protein of Mycobacterium leprae. (PubMed, Comput Biol Chem) - "Subsequent molecular dynamics simulations, MM-PBSA/GBSA and PCA analysis confirmed the stability of the protein-ligand complexes. Computational and AI-driven approaches demonstrated the potential biological role of ML0099 and identified the repurposed drugs Zileuton and Glipizide as promising inhibitors, providing a robust foundation for future experimental validation and therapeutic development."

Journal

The ALOX5-Mitochondrial oxidative stress link in quercetin-mediated nasal epithelial barrier protection in allergic rhinitis. (PubMed, Biochem Biophys Res Commun) - "These findings suggest that an ALOX5-associated mitochondrial oxidative stress pathway contributes to HDM-induced nasal epithelial barrier dysfunction. Quercetin may protect epithelial barrier integrity in AR, at least partly by suppressing ALOX5/LTB4 signaling and mitochondrial oxidative injury."

Journal • Allergic Rhinitis • Immunology • Inflammation • ALOX5 • CDH1 • TJP1

AI-guided CRISPR screening reveals therapeutic targets in psoriasis. (PubMed, Nat Commun) - "Topical zileuton, an ALOX5 inhibitor, and cligosiban, an OXTR antagonist, suppress imiquimod-induced psoriasiform dermatitis in mice, mirroring systemic anti-IL17RA antibody efficacy. By linking AI- guided selection to genetic perturbation screening, this study provides an efficient route from candidate gene nomination to biological validation and therapeutic discovery."

Journal • Dermatitis • Dermatology • Immunology • Psoriasis • IL17A

Effect of 5-lipoxygenase protein expression in malignant breast cancer cells and mechanisms involved in tumor suppression. (PubMed, J Toxicol Environ Health A) - "Further, zileuton suppressed colony formation in both breast cancer cell lines. Data suggest that 5-LOX may serve as a potential therapeutic target for breast cancer, and zileuton warrants further investigation as a candidate anti-cancer agent."

Journal • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • Women's Health • LOX

The dual role of leukotrienes in the tumor microenvironment: balancing pro-tumorigenic and anti-tumor immunity. (PubMed, Cancer Biol Ther) - "In preclinical models, pharmacological agents including montelukast, zileuton, and FLAP antagonists suppress tumor growth, and restore apoptotic signaling; current clinical evidence remains largely observational and pharmacoepidemiologic. Targeting this pathway represents a promising avenue in oncology, with potential to enhance precision medicine through biomarker-guided patient stratification. Further clinical validation is warranted to translate these findings into therapeutic benefit."

Biomarker • Journal • Review • Immune Modulation • Immunology • Oncology • HIF1A

Acute plant-derived C18 fatty acid exposure was associated with changes in muscle 5-LOX protein abundance and volatile profiles in triploid rainbow trout (Oncorhynchus mykiss). (PubMed, Food Chem (Oxf)) - "Using an acute oral gavage model, trout received oleic, linoleic, or α-linolenic acid, alone or with the selective 5-LOX inhibitor zileuton...These results indicate that acute plant-derived C18 fatty acid exposure was associated with changes in detectable muscle 5-LOX protein abundance and volatile profiles in triploid rainbow trout. The inhibitor-associated volatile changes further support the possibility that multiple oxidative processes may be involved under these acute conditions."

Journal • LOX

Synthetic heterocyclic scaffolds relevant to human 15-lipoxygenase-2 (h15-LOX-2) inhibition: Scaffold diversity, structure-activity relationships, selectivity challenges, and future directions. (PubMed, Eur J Med Chem) - "Critically, while zileuton remains the sole clinically approved lipoxygenase-targeting drug, it is clinically used as a 5-LOX inhibitor for asthma and is not an h15-LOX-2-targeted therapy...Outstanding challenges including the scarcity of ex vivo validated compounds, species-specific translational barriers arising from divergent murine ortholog function, and the absence of wild-type inhibitor co-crystal structures are critically evaluated. Future directions encompassing covalent inhibitor strategies, PROTAC-based targeted degradation, and selective modulation of the pro-ferroptotic h15-LOX-2/PEBP1 complex are discussed as promising avenues to fully realize the therapeutic potential of this target."

Journal • Review • Asthma • Atherosclerosis • Cardiovascular • Immunology • Oncology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • ALOX15B • PEBP1

Myeloid cell 5-lipoxygenase activation and its metabolite product 5-HETE promote systemic inflammation and hepatocyte ferroptosis in acute-on-chronic liver failure (EASL 2026) - "Oral zileuton was tested in LPS/D-GalN and ConA murine liver failure... Myeloid 5-LOX activation is tightly linked to systemic inflammation and severity in ACLF, and 5-HETE associates with hepatocyte ferroptosis, supporting 5-LOX as a therapeutic target."

Fibrosis • Hepatology • Inflammation • Liver Failure • ATF4

Exploration and validation of potential diagnostic biomarkers of PANoptosis in periodontitis using bioinformatics approaches. (PubMed, Biochem Biophys Res Commun) - "This study provides new evidence linking PANoptosis to periodontitis. ALOX5, CDK5R1, MMP14 and JAK3 were identified as PANoptosis-related biomarkers and potential therapeutic targets. These findings support the precision diagnosis and treatment of periodontitis."

Biomarker • Journal • Dental Disorders • Inflammation • Periodontitis • ALOX5 • JAK3 • MMP14

Editorial Note: Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer's Disease with Plaques and Tangles. (PubMed, PLoS One) - No abstract available

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Integrated physicochemical profiling, metabolomics and 5-lipoxygenase docking: a comparative analysis of naturally matured acacia honey versus commercial samples. (PubMed, Food Chem) - "Integrated computational approaches and in vitro assays confirmed some MH-enriched metabolites strongly bind 5-LOX with higher affinity than zileuton and inhibit its activity (IC₅₀:72.2 ± 19 to 291.4 ± 53 μmol/L). Phenethyl caffeate, cryptochlorogenic acid, caffeic acid serve as candidate quality markers. These findings support MH's premium quality and in vitro anti-inflammatory potential, facilitating its quality authentication and functional food development."

Journal

Molecularly diverse lonazolac-inspired pyrazole-cyanopyridin-2-one conjugates: design, synthesis, in vitro, in vivo and in silico studies as multi-target anti-inflammatory agents. (PubMed, Mol Divers) - "In the LPS-induced RAW 264.7 cell line, nitric oxide (NO) inhibitory activity revealed that 4b, 4e, and 5c were the most powerful NO inhibitors, with % inhibition of 64.97, 71.45 and 73.61, respectively, compared with indomethacin (60.97). Hybrids 4f (IC50 = 2.64 µM) and 5e (IC50 = 0.34 µM) were the most potent COX-2 inhibitors with selectivity indexes of 8.1 and 12.6, respectively, compared with Celecoxib (IC50 = 1.33 µM, SI = 4.8), while 4e and 5c were the most potent 5-LOX inhibitors, with IC50 values of 2.75 and 0.71 µM, respectively, compared to the zileuton (IC50 = 0.45 µM)...It could be preliminarily suggested that conjugates 4e and 5c could be considered as NO/5-LOX inhibitor, while conjugate 4f is a selective COX-2/5-LOX inhibitor, and 5e is a selective COX-2 inhibitor. These results indicate that 4e, 5c, and 4f are promising multitarget anti-inflammatory candidates that require further optimization."

Journal • Preclinical • Inflammation • IL1B • TNFA

Scoparone alleviates cisplatin-induced acute kidney injury by inhibiting 5-lipoxygenase-mediated ferroptosis. (PubMed, Toxicol Appl Pharmacol) - "Pharmacological inhibition of ALOX5 with zileuton recapitulated these protective effects, with no additional benefit from co-treatment. Altogether, the findings of this study show that scoparone ameliorates cisplatin-induced AKI by suppressing ALOX5-mediated ferroptosis, positioning ALOX5 as a potential therapeutic target and supporting scoparone as a promising therapeutic candidate for AKI management."

Journal • Acute Kidney Injury • Cardiovascular • Nephrology • Oncology • Renal Disease • ALOX5

Novel Pyrazole-3-Cyano-2-Pyridinone Hybrids as Multitarget Anti-Inflammatory Agents: Synthesis, Computational Modeling, and Biological Evaluation. (PubMed, Drug Des Devel Ther) - "Compound 5g most effectively suppressed PGE2 production (IC5 0 = 152.7 pg/mL), while 5m markedly reduced TNF-α levels, comparable to ibuprofen. In LOX assays, compound 5f showed potent inhibition of both 5-LOX (IC5 0 = 0.34 µM) and 15-LOX (IC5 0 = 0.21 µM), outperforming zileuton...In silico pharmacokinetic analysis predicted good oral bioavailability and drug-like properties. The synthesized pyrazole/3-cyano-2-pyridinone hybrids demonstrated promising multi-target anti-inflammatory activity with favorable safety and pharmacokinetic profiles, highlighting their potential as lead candidates for further development."

Journal

Zileuton, 5-lipoxygenase blocker, modulates acute inflammatory response in Nile tilapia. (PubMed, Dev Comp Immunol) - "No clinical adverse effects were observed. To our knowledge, this is the first demonstration in fish that oral 5-LOX inhibition by zileuton mitigates acute inflammatory reaction, and underscores leukotriene pathway as a promising lever for improving fish health outcomes."

Journal • Inflammation • A2M • APOA1 • HP

Design, synthesis, in vitro, and in silico evaluation of multi-functionalized pyrimidines as potential multitarget-directed anti-inflammatory agents. (PubMed, Bioorg Chem) - "In this study, a library of pyrimidine derivatives (5a-c, 6, 7a-n) was designed, synthesized, and examined for their in vitro potential to inhibit the activities of COX-1 and COX-2, with comparisons made to the well-known COX inhibitors celecoxib and diclofenac sodium...Compound 6 demonstrated enhanced 5-LOX inhibitory activity (IC50 = 0.235 μM) compared to the reference zileuton (IC50 = 0.334 μM)...A molecular docking study explored the binding interactions between newly synthesized inhibitors and the active sites of COX-2 and 5-LOX. Additionally, various online tools were utilized to assess the pharmacokinetics, drug likeness, and toxicity of the most active compounds."

Journal • Preclinical • IL6

Stability-Indicating Assay of Novel 5-(Hydroxamic acid)methyl Oxazolidinones with 5-Lipooxygenase Inhibitory Activity. (PubMed, Pharmaceuticals (Basel)) - "Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases... The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82-90%) but unstable in acidic, basic, and oxidative conditions. The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases."

Journal • Allergy • Oncology

Inhibiting Arachidonate-5-lipoxygenase expression ameliorates osteoarthritis progression by suppressing ferroptosis via the JAK2/STAT3 signaling pathway. (PubMed, Free Radic Biol Med) - "In summary, our study demonstrated knockdown of Alox5 inhibited the JAK2/STAT3 signaling, thereby suppressing ferroptosis and alleviating cartilage damage.Intra-articular injection of the ALOX5 inhibitor Zileuton or AAV-ShAlox5 in the knee joint alleviated cartilage damage in the mouse DMM model.Mechanistically, our study reveals that the JNK-p53-ALOX5 signaling axis alleviates OA by regulating ferroptosis in chondrocytes."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ALOX5 • IL1B

Lauric acid modulates the cyclooxygenases and nitric oxide pathways and reduces oxidative stress in preventing tracheal hyperresponsiveness in asthmatic Wistar rats. (PubMed, Front Pharmacol) - "A reduction in the contractile reactivity to CCh was observed in the asthmatic group in the presence of indomethacin, zileuton, L-NAME, apocynin, and tempol, inhibitors of COX, 5-LOX, NOS, NADPH oxidase, and a mimetic of superoxide dismutase (SOD), respectively. Treatment with lauric acid at a dose of 25 mg/kg prevented all of these alterations, except for the reduction in GSH levels. In conclusion, LA reduces tracheal hyperresponsiveness in Wistar rats with allergic asthma by negatively modulating both the COX and NO pathways and oxidative stress imbalance."

Journal • Preclinical • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Development of novel salicylic acid derivatives with dual anti-inflammatory and anti-arthritic potentials: synthesis, in vitro bio-evaluation, and in silico toxicity prediction with molecular modeling simulations. (PubMed, RSC Adv) - "These results exhibited superior activity compared to Aspirin, which had IC50 values of 11.21 ± 0.12 and 8.45 ± 0.05 µg mL-1, while demonstrating competitive activity relative to Naproxen (IC50 = 8.13 ± 0.14 and 6.18 ± 0.04 µg mL-1) and Indomethacin (IC50 = 7.16 ± 0.05 and 5.47 ± 0.04 µg mL-1) for COX-1 and COX-2, respectively...This value is comparable to that of naproxen (IC50 = 9.65 ± 0.17 µg mL-1) and zileuton (IC50 = 8.43 ± 0.05 µg mL-1), while demonstrating greater efficacy than aspirin (IC50 = 13.68 ± 0.13 µg mL-1)...Finally, in silico toxicity predictions were conducted, demonstrating a safer profile compared to the utilized drugs. Additionally, docking simulations were performed for the most active derivatives, revealing higher binding affinities, supported by hydrogen bonding, arene-cation interactions, and hydrophobic interactions."

Journal • Preclinical

Zileuton nanocrystals alter intestinal phase I/II metabolic enzymes and epithelial permeability in a sex-dependent manner. (PubMed, Drug Metab Dispos) - "Approximately 5% of asthmatic patients develop hepatocytotoxicity due to zileuton treatment and show several fold elevated levels of ALT in plasma. In the present study, differences in the decrease of ALT levels between the formulations highlight the advantages of the nanocrystal formulation."

Journal • P1/2 data • Asthma • Gastrointestinal Disorder • Immunology • Pulmonary Disease • Respiratory Diseases