zafirlukast / Generic mfg. - LARVOL DELTA

The Direct and Potentiating Antimicrobial Activities of Zafirlukast. (PubMed, Antibiotics (Basel)) - "Zafirlukast has many attractive antimicrobial activities, which may encourage further investigations in this field. However, it should be noted that it may represent a safe starting scaffold, and further chemistry is likely to be needed for it to be used in the antimicrobial setting."

Journal • Infectious Disease

Evaluating the Impact of Leukotriene Receptor Antagonists on Postoperative Acute Kidney Injury: A Retrospective Study. (PubMed, Anesth Analg) - "Perioperative use of leukotriene receptor antagonists was not significantly associated with a lower risk of postoperative AKI following oncologic surgery. Further prospective and mechanistic studies are needed to clarify whether leukotriene receptor antagonists exert renoprotective effects in surgical patients."

Journal • Retrospective data • Acute Kidney Injury • Anesthesia • Critical care • Inflammation • Nephrology • Renal Disease

Leukotriene Receptor Antagonists Inhibit SLC19A1 and SLC46A1-Mediated Transport of Folic Acid and Antifolates. (PubMed, Chem Biol Interact) - "In vitro studies showed that MK571, montelukast, zafirlukast, and pranlukast concentration-dependently inhibited SLC19A1 and SLC46A1-mediated uptake of folic acid, methotrexate, and pemetrexed, with IC50 values ranging from 2.34 to 31.8 μM for SLC19A1 and 2.79 to 45.4 μM for SLC46A1. Taken together, this study identified LTRAs as novel and potent inhibitors of the key folate transporters SLC19A1 and SLC46A1, and uncovered previously unrecognized transporter-mediated drug-drug interactions between LTRAs and folate-related agents. These findings highlight the necessity of careful clinical monitoring and potential dose adjustments during concurrent administration to ensure therapeutic safety and efficacy."

Journal • Allergic Rhinitis • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Computational identification of candidate ST2-binding bioactive compounds as putative modulators for severe type 2-high asthma. (PubMed, Comput Biol Chem) - "Sixteen compounds, including fifteen phytochemicals and one reference drug Zafirlukast, were screened against the ST2 receptor...Density functional theory analysis indicated a moderate HOMO-LUMO energy gap, providing supportive information on molecular reactivity and electronic stability. Hence, the findings prioritize Hesperetin for further experimental investigation as a candidate ST2-binding compound; however, receptor binding, functional IL-33/ST2 pathway inhibition, efficacy, and safety require validation through in vitro and in vivo studies."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • IL33

Comparative analysis of adverse drug reaction reports for leukotriene receptor antagonists mainly indicated for allergic rhinitis and asthma: a WHO VigiAccess study. (PubMed, Front Med (Lausanne)) - "Real-world evidence from spontaneous-report databases suggests differences in the safety-reporting profiles of montelukast, pranlukast, and zafirlukast. However, under-reporting and incomplete clinical information preclude estimation of incidence or causal inference; these findings should be interpreted as safety signals."

Adverse drug reaction • Journal • Allergic Rhinitis • Asthma • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Mental Retardation • Psychiatry • Pulmonary Disease • Respiratory Diseases • Suicidal Ideation

Intrinsic AIE drug nanocrystals enable imaging-guided orchitis theranostics. (PubMed, Mater Today Bio) - "Here, we show that three clinically approved leukotriene receptor antagonists, namely Pranlukast, Zafirlukast, and Montelukast can be transformed into self-reporting, self-delivering, and self-therapeutic nanotheranostics. In a rat model of acute orchitis, AIE imaging reveals efficient testicular accumulation, which correlates with attenuated histopathological damage, restored oxidative stress balance, and downregulation of the TLR4/MyD88/NF-κB and PK2/PKR1 pathways, with no obvious adverse effects on the measured short-term reproductive indices (sperm morphology and testosterone levels) observed within the experimental timeframe. This strategy converts old drugs into minimal-excipient, self-monitoring AIE nanotheranostics for imaging-guided orchitis therapy."

Journal • MYD88 • TLR4

Assessment of the binding characteristics of three antagonists toward CysLTR1 by affinity chromatography. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "The association equilibrium constants were measured as montelukast zafirlukast > pranlukast, which were correlated to the inhibition potencies of montelukast < zafirlukast < pranlukast to CysLTR1. Additionally, thermodynamic analysis in combination with molecular docking indicated that the three antagonists were spontaneously bound to CysLTR1 and their bindings were mainly driven by hydrogen bonds and van der Waals forces. Our work demonstrated that affinity chromatography can be utilized to evaluate the binding characteristics of ligand-receptor based on their retention behaviors, aiding the selection of the best ligands for further studies to become a drug molecule."

Journal

Intra-cluster receptor density (IRD): A molecular switch for TNFR1 clusters' signaling. (PubMed, Sci Adv) - "Reducing IRD through membrane tension, zafirlukast, actin depolymerization, or cholesterol depletion suppresses sTNF-α signaling, whereas increasing IRD by lowering membrane tension or exposing cells in a 3D gel-like microenvironment triggers ligand-independent activation. These findings reveal IRD as a key regulator of receptor signaling, with potential relevance across related receptor families and innovative strategies in modulating TNFR1 signaling."

Journal • Oncology • TNFA • TNFRSF1A

Zafirlukast Exacerbates Behavioral Seizure Activity and Blood-Brain Barrier Disruption Despite Modestly Reducing Neuronal Injury Markers in a PTZ-Induced Early Epileptogenesis Mouse Model. (PubMed, Mol Neurobiol) - "These findings indicate a complex role for leukotriene signaling during early epileptogenesis. Further studies using different doses, vehicles, and experimental models are warranted to clarify the effects of zafirlukast on the mechanisms underlying early epileptogenesis."

Biomarker • Journal • Preclinical • CNS Disorders • Epilepsy • Inflammation • GFAP • IL1B • MMP9 • TGFB1

Structure-based design of the approved drug zafirlukast identifies HLC40 as a potent WDR5 WIN-site inhibitor with antitumor efficacy. (PubMed, Bioorg Chem) - "Consistent with these findings, HLC40 exhibited potent antiproliferation efficacy (IC50 = 7-8 μM) in AML cells and demonstrated significant efficacy in the MV4-11 xenograft model (TGI = 49.1% @ 30 mg/kg). Collectively, these results highlight that HLC40 is a promising WDR5-targeting candidate with high therapeutic potential for hematologic malignancies."

Journal • Acute Myelogenous Leukemia • Asthma • Hematological Disorders • Hematological Malignancies • Immunology • Oncology • Respiratory Diseases • WDR5

An In Silico and In Vitro Approach Identified Potential Trypanothione Synthetase Inhibitors with Trypanocidal Activity. (PubMed, Molecules) - "Tadalafil, Zafirlukast, Raltegravir, and Olmesartan had better trypanocidal activity than the reference drugs Benznidazole and Nifurtimox in the in vitro evaluation against the trypomastigote form. Therefore, the results encourage the use of these drugs to develop new anti-T. cruzi agents."

Journal • Preclinical

Leukotriene receptor antagonists and eosinophilic granulomatosis with polyangiitis: a disproportionality analysis from FAERS, JADER, CVAR databases integrated with network pharmacology. (PubMed, PLoS One) - "Our study revealed LTRAs could increase the risk of EGPA, and initially explored potential genes and mechanisms of LTRAs-induced EGPA. It is helpful for clinicians to be alerted to the risk of EGPA during LTRAs administration."

Journal • Eosinophilic Granulomatosis With Polyangiitis • Immunology • Langerhans Cell Histiocytosis • Rare Diseases • Vasculitis • EDN1 • HMOX1 • KDR • OCLN • PACERR • PTGS2

Activation of TMEM175 lysosomal ion channels by CysLT1 receptor antagonists. (PubMed, Am J Physiol Cell Physiol) - "DCPIB, zafirlukast, and pranlukast activated TMEM175 independently of AKT activation, whereas the AKT inhibitor MK2206 partially inhibited montelukast-dependent TMEM175 activation. Not only did T119A and H449A mutations decrease apparent potencies of DCPIB, zafirlukast, and montelukast, but the T119A mutation produced a constitutively open channel phenotype. This study adds zafirlukast to the short list of moderately potent TMEM175 activators and identifies a region of the channel that contributes to activation gating."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

In Silico identification of inhalable small-molecule IL-33/ST2 antagonists for severe type-2-high asthma endotypes. (PubMed, Sci Rep) - "Zafirlukast emerged as the top-ranked scaffold with a docking score of - 7.3 kcal/mol...Collectively, these results prioritize a non-biologic, ST2-directed small-molecule scaffold for further investigation and provide a computational framework to support subsequent experimental validation, including biochemical and cellular studies, in the context of severe type-2-high asthma. As this is a purely in silico study, the findings are hypothesis-generating and do not demonstrate functional inhibition of the IL-33/ST2 interaction; experimental validation is required."

Journal • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases • IL33

Sine oculis homeobox 1 drives endothelial dysfunction in preclinical pulmonary arterial hypertension. (PubMed, Sci Transl Med) - "Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)-induced PH mice...Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity...Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development."

Journal • Preclinical • Cardiovascular • Hypertension • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EDN1 • MAPK1 • MAST4 • SIX1

Isoquercetin and Zafirlukast Cooperatively Suppress Tumor Growth and Thromboinflammatory Signaling in a Xenograft Model of Ovarian Cancer. (PubMed, FASEB J) - "ISOQ also potentiated standard cisplatin/gemcitabine chemotherapy. Notably, the combination of low-dose ISOQ plus ZAF achieved ≥ 80% inhibition of key tumor-associated markers at one-third the monotherapy dose and outperformed either agent alone. These findings support ISOQ and ZAF as promising agents for the treatment of cancer and CAT and establish thiol isomerase inhibition as a strategy to simultaneously target thrombosis, tumor progression, and immune escape."

IO biomarker • Journal • Preclinical • Cardiovascular • Hematological Disorders • Oncology • Ovarian Cancer • Solid Tumor • Venous Thromboembolism • PDIA3 • PD-L1

Early AI-driven repurposing study of existing drugs towards the vasopressin V2 receptor. (PubMed, Comput Biol Med) - "Five drugs were shortlisted as promising candidates for V2R: cabergoline, clopidogrel, cloxacillin, perphenazine, and zafirlukast...Interestingly, zafirlukast, at single-digit nanomolar concentration significantly reduced the DDAVP-dependent cAMP production and water reabsorption, with effects comparable to tolvaptan, a well-known selective V2R antagonist...Induced-fit docking simulations demonstrated that zafirlukast engages V2R by adopting a binding conformation closely resembling that of X-ray solved vasopressin. Taken together, our results support the repurposing of zafirlukast as a promising V2R antagonist candidate."

Journal • Oncology • CD4

Discovery of Essential Genes as Possible Targets for Prostate Cancer Drug Development. (PubMed, Int J Genomics) - "Following that, we considered these possible genes as targets for drugs, performed docking analysis with 255 meta-drug agents, and identified the top 10 candidate drugs (adapalene, ergotamine, imatinib, dutasteride, vistusertib, risperidone, zafirlukast, irinotecan hydrochloride, drospirenone, and telmisartan). This study uniquely combines multidataset transcriptomic integration, HubG prioritization, and MD validation to propose novel biomarker-drug pairings for PCa. The findings offer promising leads for future experimental and clinical validation."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BIRC5 • CDCA5 • NUSAP1

An ELISA for discovering protein-protein interaction inhibitors: blocking lysinoalanine crosslinking between subunits of the spirochete flagellar hook as a test case. (PubMed, SLAS Discov) - "Screening a library of ∼700 compounds with the ELISA confirmed that hexachlorophene, currently the only known inhibitor of Lal crosslinking in FlgE, effectively inhibits the crosslinking reaction. In addition, the assay identified two new potential inhibitors, honokiol and zafirlukast, and several activators which belong to well-known classes of antibiotics."

Journal • Developmental Disorders • Infectious Disease

Cysteinyl leukotriene receptor 1 regulates cellular glucose levels in human retinal cells. (PubMed, Mol Vis) - "Primary human ECs, PCs, and the ARPE-19 cell line were cultured under standard (5.5 mmol/l glucose + 27.5 mmol/l mannitol) and high-glucose (33.0 mmol/l) conditions in the absence and presence of the specific CysLTR1 antagonists montelukast and zafirlukast for 1, 3, and 7 days. Interestingly, the effect of CysLTR1 activity on glucose levels was reversed under acute metabolic stress. Thus, the activity of CysLTR1 appears to be more complex in terms of glucose metabolism and needs to be studied in more detail."

Journal • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Retinal Disorders • Type 2 Diabetes Mellitus

An ELISA for discovering protein-protein interaction inhibitors: blocking lysinoalanine crosslinking between subunits of the spirochete flagellar hook as a test case. (PubMed, bioRxiv) - "Screening a library of ∼700 compounds with the ELISA confirmed that hexachlorophene, currently the only known inhibitor of Lal crosslinking in FlgE, effectively inhibits the crosslinking reaction. In addition, the assay identified two new potential inhibitors, honokiol and zafirlukast, and several activators which belong to well-known classes of antibiotics."

Journal • Infectious Disease

LC-MS-based metabolomics revealed promising role of leukotriene receptor antagonists against colorectal cancer. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "These findings demonstrate the antiproliferative potential of montelukast and zafirlukast in CRC and provide new insights into their distinct molecular mechanisms of action. This supports their potential repurposing as adjunctive therapies in CRC treatment."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor

Structural elucidation of Langat virus helicase unveils dual-target inhibition for broad-spectrum anti-flaviviruses strategy. (PubMed, Front Cell Infect Microbiol) - "Zafirlukast emerges as a promising prototype for dual-target inhibitors, capable of simultaneously obstructing ATP hydrolysis and RNA unwinding. These findings provide a strong foundation for designing novel broad-spectrum therapeutics against neurotropic flaviviruses."

Journal • Dengue Fever • Infectious Disease

Radical-induced Lipid Oxidation Produces a Torrent of Leukotriene-like Agonists in Severe Asthma. (PubMed, J Allergy Clin Immunol) - "Urinary øLTs are new biomarkers that may facilitate non-invasive assessment of asthma severity and the efficacy of therapeutic measures. Presumably øLTs contribute to CysLT receptor-mediated inflammation through CysLT-like inflammatory biological activities previously ascribed uniquely to CysLTs. øLTs provide a mechanistic link between radical-induced biochemistry, activation of the ERK/Akt pathway and asthma. These discoveries require re-examination of long-held disease paradigms for the involvement of CysLTs in asthma pathology and reconsideration of the mechanistic basis for the efficacy of CysLT receptor antagonists for ameliorating chronic asthma. Inhibiting the biosynthesis of øLTs may provide new therapeutic strategies for preventing asthmatic inflammation."

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

A conserved mechanism of LRRC8 channel inhibition by two structurally distinct drugs. (PubMed, Commun Biol) - "We employed a structurally defined homomeric channel chimera (8C-8A(IL125)) and heteromeric LRRC8A/LRRC8C (8A/8C) channels to investigate the mechanism of action of two structurally distinct LRRC8 inhibitors: zafirlukast and pranlukast. The association between voltage-dependent inactivation induced by mutations or low pH and inhibitor sensitivity suggests that drug inhibition involves disruption of protein-lipid interactions and destabilization of the pore. This may represent a common mechanism of LRRC8 channel inhibition by lipophilic drugs."

Journal • LRRC8A