tilarginine (L-NMMA) / Arginox Pharma, Houston Methodist Research Institute, Obsidian - LARVOL DELTA

: Vascular Function in Health and Disease (clinicaltrials.gov) - P1 | N=420 | Recruiting | Sponsor: D. Walter Wray | Trial completion date: Aug 2026 ➔ Aug 2030 | Trial primary completion date: Aug 2026 ➔ Aug 2030

Trial completion date • Trial primary completion date • Cardiovascular • Chronic Obstructive Pulmonary Disease • Heart Failure • Hypertension • Immunology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Impairment of circulating metabolites induces endothelial dysfunction in adolescents exposed to gestational diabetes in utero (ESC 2026) - "Endothelium-dependent (EDR) and -independent (EIR) relaxations to acetylcholine (10-9 to 10-4,5 M) and sodium nitroprusside (10-10 to 10-5,5 M) with and without antioxidants Tempol (10-4 M) or NAC (10-5 M) were assessed by wire myography...Levels of N-monomethylarginine (NMMA), a NO synthase inhibitor, were increased, whereas 3-hydroxyanthranilic acid (3-HAA), a metabolite with anti-inflammatory properties, was decreased... Our results demonstrate that adolescents exposed to GD in utero exhibit an altered circulating metabolome that impairs endothelial function, potentially contributing to their elevated ASCVD risk. This metabolic imbalance may represent a putative target to mitigate ASCVD risk in this population."

Atherosclerosis • Cardiovascular • NOX4

Phase IB/II Trial of Alpelisib with iNOS Inhibitor and Nab-paclitaxel in Patients with HER2 negative Metastatic or Locally Advanced Metaplastic Breast Cancer (SABCS 2024) - "Through combined blockade of iNOS and PIK3CA, with L-NMMA and alpelsib, along with nab-paclitaxel chemotherapy, we aimed to improve outcomes for patients with metastatic or locally advanced MpBC. In this highly refractory group of patients, this novel, rationally designed therapy has shown remarkable efficacy, not previously demonstrated in MpBC, including some sustained responses, particularly in those subjects with PIK3CA mutations. Equally as important, the regimen was also found to be safe and tolerable, as we begin the multi-center phase II portion of this trial."

Clinical • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • HIF1A • PIK3CA

Bioactive alkaloids from the stems of Piper magen, an edible spice in Yunnan, China. (PubMed, Fitoterapia) - "Magenamide C and 5,6-dihydro-1-[(2E)-3-(4-methoxyphenyl)-1-oxo-2-propen-1-yl]-2(1H)-pyridinone (15) strongly inhibited NO production, with IC50 values of 30.09 μM and 3.16 μM, respectively (positive control: L-NMMA, IC50 = 42.24 μM). Compound 15 and magenamide A demonstrated protective effects against corticosterone-induced neuronal injury at a concentration of 2 μM (P < 0.001). 1-(m-Methoxycinnamoyl)pyrrolidine (16) exhibited BACE1 inhibitory activity, with an IC50 value of 8.73 μM (positive control: LY2886721, IC50 = 31.80 nM)."

Journal

The Impact of Age and Exercise Training on Endothelial-Mediated Mechanisms of Vasodilation during Passive Leg Movement in Males. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "Interrogation of these vasodilatory pathways were assessed by PLM under three conditions: control (CON), inhibition of NOS alone (NG-monomethyl-l-arginine; L-NMMA), and combined inhibition of NOS, cyclooxygenase (ketorolac tromethamine; KET) and cytochrome P450 (fluconazole; FLUC) (L-NMMA+KET+FLUC). Neither L-NMMA nor L-NMMA+KET+FLUC attenuated the PLM vasodilatory response in older males before or after exercise training (P=0.68 and P=0.51, respectively). Together, these results indicate 8 weeks of single-leg knee-extension exercise training improves the vasodilatory response to PLM in younger, but not older males, and does not alter the contribution of NO or the combined contribution of PG and EETs to PLM-induced vasodilation."

Journal

An undescribed alkaloid from Crinum latifolium L.: structural elucidation and evaluation of its biological activity. (PubMed, Nat Prod Res) - "Among them, ungeremine (4) exhibited the most potent AChE inhibitory activity, with an IC50 value of 0.39 ± 0.03 µM, which was significantly stronger than that of the positive control galantamine (IC50 = 2.40 ± 0.45 µM). (+)-Crinamine (3) demonstrated notable anti-inflammatory and cytotoxic activities, showing an IC50 value of 0.85 ± 0.04 µM for NO inhibition (positive control L-NMMA, IC50 = 7.80 ± 0.36 µM), and IC50 values of 11.82 ± 1.09 µM and 10.38 ± 0.82 µM against HepG2 and LNCaP cell lines, respectively. The new alkaloid, 1-hydroxy-ungeremine (1), displayed moderate AChE inhibitory activity (IC50 = 12.24 ± 1.08 µM). These findings further support C. latifolium as a valuable source of bioactive Amaryllidaceae alkaloids with potential therapeutic applications."

Journal • Pain

Cinnamolides A-G, seven previously undescribed phytoconstituents from the peels of Cinnamomum chago and their anti-inflammatory activity. (PubMed, Phytochemistry) - "Compound 1 exhibited the strongest inhibitory activity, with an IC50 value of 3.6 μM, which is more potent than the positive control, N-Monomethyl-L-arginine (L-NMMA, IC50 = 33.0 μM). Furthermore, compound 1 can reduce the levels of the pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β) and downregulate nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression."

Journal • Oncology • IL1B • IL6 • PTGS2 • TNFA

A molecular perspective on dimethylarginine dimethylaminohydrolases structure and function. (PubMed, Biochem J) - "Asymmetric dimethylarginine (ADMA) and monomethylarginine (L-NMMA) are endogenous NOS inhibitors whose accumulation leads to cardiovascular, renal, and neurodegenerative diseases. Dimethylarginine dimethylaminohydrolase (DDAH) converts ADMA and NMMA to L-citrulline and dimethylamine or monomethylamine, respectively, thereby controlling NO bioavailability...On the other hand, the assessment of DDAH2 function is still to be defined. The present review summarizes current molecular, biochemical, and structural insights into DDAH isoforms and discusses their potential as pharmacological targets for diseases associated with altered NO signaling."

Journal • Review • Cardiovascular • CNS Disorders • DDAH2

Liguladentatanes A-E, five undescribed highly oxygenated bisabolene-type sesquiterpenoids from Ligularia dentata and their anti-inflammatory activity. (PubMed, Fitoterapia) - "Notably, compound 7 showed a remarkable anti-inflammatory effect with an IC50 value of 14.99 μM, which outperformed that of the positive control (L-NMMA, IC50: 20.70 μM)...The finding suggested that these bisabolene-type sesquiterpenoids may exert their anti-inflammatory activity by targeting EGFR and PTGS2. This study not only expands the chemical diversity of L. dentata, but also highlights a promising structural motif for the development of anti-inflammatory agents."

Journal • Inflammation • Pain • EGFR • IL1B • IL6 • PACERR • PTGS2 • TNFA

Laggeranines FI, four undescribed sesquiterpenoids from Laggera pterodonta and their inhibitory effects on NO production in RAW 264.7 macrophages. (PubMed, Fitoterapia) - "Notably, Laggeranine H (3) displayed significant activity with an IC₅₀ value of 4.80 ± 0.16 μM, surpassing the positive control L-NMMA (23.12 ± 4.17 μM). Further mechanistic studies revealed that Laggeranine H exerts anti-inflammatory effects by suppressing IκBα phosphorylation and degradation, thereby inhibiting NF-κB p65 activation and subsequent iNOS expression. These findings expand the chemical diversity of L. pterodonta and provide experimental evidence supporting its traditional use as an anti-inflammatory agent."

Journal • Inflammation • NFKBIA

Bioactive Metabolites from the Cultured Lichen Mycobionts of Astrothelium straminicolor and Nigrovothelium inspersotropicum. (PubMed, Planta Med) - "Notably, compounds N1: -N3: showed significant inhibitory effects on NO production, with IC50 values ranging from 14 to 25 µM, compared with the positive control L-NMMA (IC50 = 49 µM). Further molecular docking clarified the inhibitory mechanism of the active compounds."

Journal

Nitric oxide-dependent stabilization of vimentin confers chemoresistance in ovarian cancer. (PubMed, Mol Ther Nucleic Acids) - "Mechanistically, L-NMMA-mediated inhibition of iNOS signaling reduced S-nitrosylation, accelerated vimentin ubiquitination, and promoted its proteasome-dependent degradation. These findings identify iNOS-mediated S-nitrosylation as a key regulator of vimentin stability and EMT and suggest that therapeutic inhibition of NO signaling may increase cisplatin sensitivity in HGSC and improve patient outcomes."

Journal • Platinum resistant • Breast Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • Targeted Protein Degradation • VIM

Phase Ib of L-NMMA and Pembrolizumab (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: The Methodist Hospital Research Institute | Active, not recruiting ➔ Completed

dMMR • IO biomarker • Mismatch repair • MSI-H • Trial completion • Tumor mutational burden • B Cell Lymphoma • Bladder Cancer • Cervical Cancer • Classical Hodgkin Lymphoma • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Hepatocellular Cancer • Hodgkin Lymphoma • Large B Cell Lymphoma • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Lymphoma • Melanoma • Merkel Cell Carcinoma • Microsatellite Instability • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Non-melanoma Skin Cancer • Oncology • Primary Mediastinal Large B-Cell Lymphoma • Renal Cell Carcinoma • Skin Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer • BRAF • MSI • PD-L1 • TMB

Obsidian Therapeutics and Galera Therapeutics Announce Merger Agreement and $350 Million Concurrent Private Placement (Businesswire) - "In support of the transaction, Galera and Obsidian have secured commitments for an oversubscribed private placement financing that is expected to result in total gross proceeds of $350 million..The combined company’s cash and cash equivalents balance at closing, including the funds from the private placement financing, is anticipated to fund the combined company’s operations into the second half of 2028 and provides runway through key clinical milestones for Obsidian’s lead product candidate, OBX-115. These include Phase 1 data from the ongoing NSCLC trial expected in the first half of 2027, and by year-end 2027, topline data from their melanoma registration-enabling trial. The combined company will also continue to support Galera’s pipeline."

M&A • P1 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Melanoma • Non Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer

Unraveling the microbiome-iNOS connection in obesity-driven triple-negative breast cancer (AACR 2025) - "- L-NMMA combined with docetaxel delayed tumor growth in both diet groups, though the untreated/treated tumor size ratio was higher in HFD mice (6.5) than ND mice (2.1). These findings suggest that HFD-induced gut microbiome alterations create a pro-inflammatory environment driving increased iNOS expression, promoting tumor aggressiveness and influencing therapeutic response. Targeting the gut microbiota, alongside iNOS inhibition, could provide novel strategies for managing obesity-associated TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NOS2

iNOS inhibition reprograms the tumor microenvironment enhancing antitumor immunity in obesity associated triple negative breast cancer (TNBC) (AACR 2025) - "This study investigates whether combining the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) with docetaxel enhances antitumor efficacy in an obese TNBC model. L-NMMA effectively remodels the obesity-altered TME, reducing tumor growth and metastasis while promoting an immune-supportive environment. Targeting iNOS with L-NMMA in combination with chemotherapy emerges as a promising therapeutic strategy to enhance TNBC treatment, particularly for obese patients."

Biomarker • IO biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL11 • CD24 • CD8 • CSF3 • IL17A • IL6 • MRC1 • TFRC • TNFA

iNOS inhibition through L-NMMA reveals immunostimulatory effects in obesity-associated triple-negative breast cancer (TNBC) tumors (AACR 2024) - "This study examines whether combining standard chemotherapy (docetaxel) with NOS inhibition via L-NMMA could reshape the TME and bolster antitumor effects in TNBC within an obese mouse model.Experimental Procedure: C57bl/6 mice, a TNBC syngeneic mouse model, were fed a high-fat diet (HFD) or normal diet (ND) for 10 weeks. Our findings indicate a distinct immunomodulatory mechanism of iNOS inhibition in HFD tumors, which displayed expression profiles marked by heightened immunosuppressive markers when compared to ND tumors. LNMMA treatment reversed this phenotype, aligning the profile closer to ND tumors. These discoveries underscore the potential of inhibiting iNOS to reshape the immune tumor microenvironment (TME) and modulate pathways linked to cell proliferation and survival."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD163 • CD4 • CTLA4 • FOXP3 • PD-1 • PD-L1

Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer (AACR 2025) - "Treatment with the Combo significantly reduced tumor growth compared to single drugs and control group. There was no statistically significant difference between the L-NMMA group and sacituzumab govitecan-treated mice. Overall, our findings demonstrate the synergism between L-NMMA and sacituzumab govitecan, highlighting the potential use of these drugs in future clinical trials."

Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Targeting NOS2 and the tumor microenvironment in endometrioid ovarian cancer: Implications for treatment and survival (AACR 2024) - "After upregulating NOS2, we tested the efficacy of Cisplatin in combination with L-NMMA, a NOS2 inhibitor, on A2780 cells through proliferation assays using RealTime-Glo™ MT Cell Viability Assay (Promega®). Taken together, our results showed the importance of a proinflammatory environment and adipose tissue in NOS2 upregulation. These findings show a potential correlation between endometriosis, obesity, and endometrioid ovarian cancer. With the development of an in vivo and in vitro model, we can gain a better understanding of the role of NOS2 in immune inactivation as well as in cell proliferation in EOC."

Biomarker • Tumor microenvironment • Oncology • Ovarian Cancer • Solid Tumor • IFNG • IL1B • NOS2 • TNFA

Targeting NOS2 and the tumor microenvironment in ovarian cancer: Switching the immune system from "cold" to "hot" (AACR 2025) - "By combining pan-NOS inhibitor L-NMMA with conventional Cisplatin administration, we want to convert the immune environment from "cold" or non-responsive to "hot" or responsive to chemotherapy. Our results showed the potential of the combination therapy to increase the infiltration of NK and NK/NKT cells and T lymphocytes into ascites together with the increase of effector markers in CD4+ T cells. The development of a second in vivo model based on the OVCAR8 NOS2 KO cell line will provide a better understanding of the role of NOS2 in the metastasis formation process and the impact of NOS2 on patients' survival."

Biomarker • Tumor microenvironment • Oncology • Ovarian Cancer • Solid Tumor • CD44 • NOS2 • VIM • ZEB1

Design, synthesis, and anti-inflammatory evaluation of forskolin derivatives with mechanistic insights. (PubMed, Nat Prod Res) - "Evaluation of anti-inflammatory measurement indicated that compound 7 exhibited a good NO inhibition effect with an IC50 value of 5.83 μM and low cytotoxicity, approaching that of the positive control, total L-NMMA...Molecular docking validation confirmed that compound 7 was bound to the target protein PPARG with a strong binding energy of -8.86 kJ mol-1. Compound 7 revealed good anti-inflammatory activity via multi-pathway synergy, thereby laying the theoretical foundation for potent agents."

Journal • IL1B • IL6 • PPARG • TNFA

FNR-like unit interacts with C-terminal related residues trigger nNOS reductase domain conformational flexibility change. (PubMed, Front Neurosci) - "In this study, we evaluated the effects of widely used nNOS inhibitors, including spermidine (Spe) and L-NMMA, on nNOS activity using cellular NO assays and Western blot analysis...Notably, R1400 and F1395, previously associated with the calmodulin-binding domain, influence conformational flexibility, while R1173 represents a novel interaction hotspot distinct from R1284. These results provide detailed insights into the dynamic mechanisms of the FNR-like unit and identify promising targets for the development of improved nNOS inhibitors to control excessive NO production in neurological disorders such as ischemic stroke."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • Reperfusion Injury

A new method for the synthesis of 6,7-dihydro-5H-pyrrolo[2,1-a][2]benzazepines and 5,6,7,9,10,11-hexahydro-12H-indolo[2,1-a][2]benzazepines and evaluation of their bioactivity. (PubMed, RSC Adv) - "Amongst these compounds, 3b-e had the best inhibitory activity against the tested cancer cell lines with IC50 values ranging from 4.52 to 19.97 µM, Notably, compound 3b demonstrated the most potent inhibitory effect on nitric oxide (NO) production, with an IC value of only slightly higher than those of the reference compound l-NMMA. Furthermore, molecular docking studies revealed the important interaction of four compounds 3b-e with residues in the etoposide-binding site of topoisomerase as well."

Journal • Oncology

Methylarginine Levels and Their Impact on Vascular Aging: A Systematic Review. (PubMed, Vasc Biol) - "Among the factors involved in this process, methylarginines, such as asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-monomethyl-L-arginine (L-NMMA), stand out...The in vitro study reinforced this evidence by demonstrating that increasing concentrations of ADMA accelerate endothelial cell senescence, reduce telomerase activity, and decrease NO production. Interpretation of the results should consider the methodological limitations of the included studies, but the findings reinforce the role of methylarginines as potential biomarkers of vascular aging and highlight the need for further investigations exploring therapeutic strategies to minimize their deleterious effects."

Journal • Alzheimer's Disease • Cardiovascular • Cognitive Disorders

A novel tetranortirucallane-type alkaloid with potential anti-inflammatory activity from Aglaia lawii. (PubMed, Nat Prod Res) - "1 possessed potent anti-inflammatory activity against NO production with IC50 values of 9.65 μM compared with the positive control NG-monomethyl-L-arginine (L-NMMA, IC50 = 33.85 μM). In addition, 1 was evaluated for cytotoxicity against five human tumour cell lines (HL-60, A-549, SMMC-7721, MDA-MB-231, and SW480), but was found to be inactive."

Journal • Oncology