KML29 / Boehringer Ingelheim - LARVOL DELTA

Radiosynthesis and Evaluation of Novel 18F Labeled PET Ligands for Imaging Monoacylglycerol Lipase (SNMMI 2025) - "Blocking experiments with KML29 led to a significant reduction of radioactivity (Figure 1D)... Compounds (R)-6 and (S)-6 were synthesized with overall yields of 5.1% and 28% over four steps, respectively (Figure 1A). (R)-6 demonstrated an IC50 of 18.57±1.09 nM, while (S)-6 exhibited superior potency with an IC50 values of 1.59±1.08 nM. Both compounds showed no significant inhibition of other lipid hydrolases."

CNS Disorders • Mental Retardation • Oncology • Pain • Psychiatry

Protective effects of KML29 in intestinal ischemia-reperfusion injury: An experimental study. (PubMed, Ulus Travma Acil Cerrahi Derg) - "In conclusion, this study demonstrated that treatment with both doses of KML29 (2.5 mg/kg and 10 mg/kg) significantly reduced the number of apoptotic cells and inflammatory markers, and improved histopathological findings in the intestinal tissues of rats subjected to IR. With its anti-inflammatory and anti-apoptotic properties, KML29 may represent a novel therapeutic option for the treatment of mesenteric ischemia."

Journal • Cardiovascular • Gastrointestinal Disorder • Oncology • Reperfusion Injury • IL1B • TGFB1 • TNFA

Discovery of new covalent inhibitors of monoacylglycerol lipase with the nitrile warhead via SCARdock. (PubMed, Bioorg Chem) - "Significantly increased 2-AG levels were detected in MDA-MB-231 cells treated with MAGL inhibitor ZQ-5, ZQ-6, ZQ-7, ZQ-19, and KML29, a previously identified MAGL covalent inhibitor. Moreover, these MAGL inhibitors inhibited the proliferation and migration of MDA-MB-231 cells. This work expands the application of SCARdock and provides meaningful clues for developing better MAGL inhibitors."

Journal • Breast Cancer • Oncology • Solid Tumor

Inhibitors of Endocannabinoids' Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice. (PubMed, Int J Mol Sci) - "Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Psychiatry • Schizophrenia

2-Arachidonoylglycerol Activity in Over Ischemia Reperfusion Damage: Can Endocannabinoids Protect Ovarian Reserve? (PubMed, Cannabis Cannabinoid Res) - "Objective: The present study aimed to demonstrate the possible effects of increased 2-arachidonoylglycerol (2-AG) by applying the monoacylglycerol lipase inhibitor KML-29 on rats with ovarian ischemia-reperfusion (IR) model... It was seen that anti-inflammatory, antioxidant, and antiapoptotic activity was formed, and the ovarian reserve was preserved with 2-AG in ovarian IR damage. The protective effect of endocannabinoids on the ovaries may create a promising new treatment strategy for many pathologies that will affect the ovarian reserve."

Journal • Cardiovascular • Oncology • Reperfusion Injury • IL1B • NF-κβ • TGFB1 • TNFA

Protective effect of fatty acid amide hydrolase inhibitor URB597 and monoacylglycerol lipase inhibitor KML29 on renal ischemia-reperfusion injury via toll-like receptor 4/nuclear factor-kappa B pathway. (PubMed, Int Immunopharmacol) - "Our results reveal that MAGL inhibitor KML29 and FAAH inhibitor URB597 have a protective effect on kidney IR injury by preventing apoptosis and inflammation. Inhibition of MAGL and FAAH may be a new therapeutic strategy to prevent kidney IR injury."

Journal • Cardiovascular • Immunology • Inflammation • Oncology • Renal Disease • Reperfusion Injury • CASP3 • IL18 • IL1B • IL6 • KIM1 • LCN2 • NF-κβ • TLR4 • TNFA

2-AG-mediated Control of GABAergic Signaling is Impaired in a Model of Epilepsy. (PubMed, J Neurosci) - "Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats...Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG mediated-retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity.SIGNIFICANT STATEMENT:The plastic reorganization of endocannabinoid (eCB) signaling after seizures and during epileptogenesis may contribute to the negative neurobiological consequences associated with seizure activity. Therefore, a deeper understanding of the molecular basis underlying the pathologic long-term eCB signaling remodelling following seizure activity will be crucial to develop novel therapies for epilepsy which not only target seizure..."

Journal • CNS Disorders • Depression • Epilepsy • Psychiatry

Neuroprotective effects of minocycline and KML29, a potent inhibitor of monoacylglycerol lipase, in an experimental stroke model: a small-animal positron emission tomography study. (PubMed, Theranostics) - "PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [C]SAR127303 for MAGL and [F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia."

Journal • Cardiovascular • Immunology • Inflammation • Metabolic Disorders

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy. (PubMed, Cells) - "Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ has been shown to be neuroprotective, treatments combining PGJ with these PG synthesis inhibitors do not enhance PGJ's neuroprotection."

Journal • Preclinical • Immunology • Inflammation • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain

Distinct Activity of Endocannabinoid-Hydrolyzing Enzymes MAGL and FAAH in Key Regions of Peripheral and Central Nervous System Implicated in Migraine. (PubMed, Int J Mol Sci) - "MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK-048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in the generation of nociceptive signals suggests this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission."

Journal • CNS Disorders • Migraine • Pain

Hippocampal 2-Arachidonoyl Glycerol Signaling Regulates Time-of-Day- and Stress-Dependent Effects on Rat Short-Term Memory. (PubMed, Int J Mol Sci) - "KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance."

Journal

The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain. (PubMed, J Pharmacol Exp Ther) - "In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. The need for effective, non-opioid based therapies is essential and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Breast Cancer • Immunology • Musculoskeletal Pain • Oncology • Pain • Solid Tumor

CB2 Receptors and Neuron-Glia Interactions Modulate Neurotoxicity Generated by MAGL Inhibition. (PubMed, Biomolecules) - "In this study, the effect of MAGL inhibition by KML29 was evaluated in two types of rat cortical primary cultures; mixed cultures, including neuron and glial cells, and neuron-enriched cultures...Our results show that neuron-glia interactions are essential for neuronal survival. CB2 receptors play a key role in these protective interactions when neurons are exposed to toxic conditions."

Journal • CNS Disorders

Cannabinoid CB receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear. (PubMed, Neuropsychopharmacology) - "A similar behavioral response was observed with another MGL inhibitor, KML29 (4 and 16 mg/kg, IP). Surprisingly, the effect of JZL184 was prevented by co-administration of the CB inverse agonist AM630 (5 mg/kg, IP), but not the CB inverse agonist rimonabant (1 mg/kg, IP)...Notably, (i) JWH133 was behaviorally ineffective in animals that had no prior experience with TMT; and (ii) CB mRNA levels in rat prefrontal cortex were elevated 7 days after exposure to the aversive odorant. The results suggest that JZL184 attenuates the behavioral consequences of predator stress through a mechanism that requires 2-AG-mediated activation of CB receptors, whose transcription may be induced by the stress itself."

Journal • Preclinical • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat. (PubMed, Neuropharmacology) - "Conversely, systemic administration of KML29 (40 mg/kg, i.p.) 2 h before IS exacerbated stress induced anxiety. MAGL inhibition in the vmPFC may promote resilience by augmenting the output of neurons that project to brainstem and limbic structures that mediate stress responses."

Journal • Preclinical

Combatting joint pain and inflammation by dual inhibition of monoacylglycerol lipase and cyclooxygenase-2 in a rat model of osteoarthritis. (PubMed, Arthritis Res Ther) - "Combination therapy of KML29 plus CXB reduced joint pain and inflammation. Thus, dual inhibition of MAGL and cyclooxygenase-2 pathways could be a useful approach to alleviate joint inflammation and pain in OA joints."

Journal • Preclinical