EX937 / Exxel Pharma - LARVOL DELTA

Inhibiting the peripheral degradation of anandamide reduces trigeminal hyperalgesia in a model of dural neurogenic inflammation via a CB1/CB2-independent mechanism (EHF-EHC 2025) - "These findings suggest a prominent role for anandamide in the pain modulation in this model of neurogenic inflammation. URB937 anti-hyperalgesic effects appear to be CB1/CB2 receptor independent activation."

CNS Disorders • Inflammation • Migraine

Peripheral Monoacylglycerol Lipase Inhibition Reduces Neuropathy and Tumor Growth in a Mouse Model (IASP 2024) - "In the current studies, we compared a peripheral MGL inhibitor LEI-515, global MGL inhibitor JZL184, and peripheral FAAH inhibitor URB937 for their abilities to suppress development of CIPN and reduce tumor size in a mouse model of breast cancer. The combination of LEI-515 with paclitaxel produced a greater reduction in tumor size than paclitaxel alone, while also suppressing mechanical and cold hypersensitivities associated with CIPN. Inhibition of MGL produces anti-cancer properties. The peripherally-restricted MGL inhibitor exhibited more promise for suppressing development of CIPN compared to the global MGL inhibitor JZL184."

Preclinical • Breast Cancer • Colorectal Cancer • Immunology • Mood Disorders • Neuralgia • Oncology • Pain • Peripheral Neuropathic Pain • Psychiatry • Solid Tumor

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia. (PubMed, Pharmaceuticals (Basel)) - "These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms."

Journal • Preclinical • Inflammation • Neuralgia • Pain

Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats. (PubMed, Psychopharmacology (Berl)) - "URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure."

Journal • Preclinical • Mood Disorders • Psychiatry

Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition. (PubMed, Exp Neurol) - "More importantly, isobolographic analyses revealed that the combination of URB937 and ARN19702 produced substantial synergistic (greater than additive) antinociceptive effects in both models as well as additive anti-inflammatory effects in the carrageenan test. Together, the findings uncover a functional interplay between FAAH and NAAA substrates in the control of nociception, which might be exploited clinically to develop safe and effective pain management strategies."

Journal • Immunology • Inflammation • Pain

Pharmacological characterisation of the CB receptor antagonist activity of cannabidiol in the rat vas deferens bioassay. (PubMed, Eur J Pharmacol) - "Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min...Similarly, SR141716 was a competitive antagonist with pK values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol's low micromolar CB antagonist pK values suggest that at clinical blood levels (1-3 μM) it may act as a CB antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline."

Journal • Preclinical

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine. (PubMed, Neurobiol Dis) - "The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways."

Journal • Preclinical • CNS Disorders • Migraine • Mood Disorders • Pain • Psychiatry

[EXPRESS] FRONT AND HIND PAW DIFFERENTIAL ANALGESIC EFFECTS OF AMITRIPTYLINE, GABAPENTIN, IBUPROFEN AND URB937 ON MECHANICAL AND COLD SENSITIVITY IN CISPLATIN-INDUCED NEUROPATHY. (PubMed, Mol Pain) - "This suggests that front paw responses across multiple modalities provide reliable and accurate information about pain-related drug effects. Future studies should be aimed at elucidating the mechanisms underlying these differential effects."

Journal • Gene Therapies • Pain

Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats. (PubMed, J Pharm Pharmacol) - "Pain remains a major unmet medical need. The favourable pharmacokinetic and pharmacodynamic properties of URB937, along with its tolerability, encourage further development studies on this compound."

Journal • PK/PD data

Fatty acid amide hydrolase inhibition in the central nervous system prevents and reverses morphine tolerance in male and female mice. (PubMed, Br J Pharmacol) - "The results support a role for central FAAH-regulated lipid signaling in the modulation of opiate tolerance, and point to FAAH as a potential target for opiate-sparing medications."

Journal • Preclinical

Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance, physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro. (PubMed, Pharmacol Res) - "Challenge with the CB antagonist rimonabant precipitated CB-dependent withdrawal in paclitaxel-treated mice receiving WIN55,212-2 but not URB597 or URB937. Neither FAAH inhibitor reduced viability of non-tumor HEK293 cells in either the presence or absence of paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce paclitaxel-induced allodynia without the occurrence of CB-dependence in vivo and may, in fact, enhance the anti-tumor actions of paclitaxel in vitro."

Journal

Inhibition of Fatty Acid Amide Hydrolase Improves Depressive-Like Behaviors Independent of Its Peripheral Antinociceptive Effects in a Rat Model of Neuropathic Pain. (PubMed, Anesth Analg) - "Inhibition of FAAH can improve depressive-like behaviors induced by neuropathic pain independent of its peripheral antinociceptive action. Enhanced neurogenesis in hippocampus might contribute to the antidepressive effects of URB597."

Journal • Preclinical

Posttreatment With the Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates One-Lung Ventilation-Induced Lung Injury in a Rabbit Model. (PubMed, J Surg Res) - "Posttreatment with the FAAH inhibitor URB937 attenuated OLV-induced lung injury in rabbits and was associated with increased AEA levels and decreased levels of AA and its downstream metabolites."

Journal • Preclinical

FAAH inhibition as a preventive treatment for migraine: A pre-clinical study. (PubMed, Neurobiol Dis) - "The findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition."

Journal

Fatty acid amide hydrolase inhibition normalises bladder function and reduces pain through normalising the anandamide/palmitoylethanolamine ratio in the inflamed bladder of rats. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "We studied the effect of the peripherally restricted fatty acid amide hydrolase inhibitor URB937 in bladder reflex activity and bladder pain using the lipopolysaccharide model of cystitis...Fatty acid amide hydrolase inhibition results in complex changes in bladder endocannabinoid levels. The therapeutic effect of fatty acid amide hydrolase inhibitors is not related to increase in anandamide levels but rather a normalisation of the anandamide and palmitoylethanolamine level ratio."

Journal • Preclinical