CRB-4001 / Corbus Pharma, Jenrin Discovery - LARVOL DELTA

CB1 receptors on a subset of vagal afferent neurons modulate voluntary ethanol intake in mice. (PubMed, Mol Psychiatry) - "We found that selectively deleting cannabinoid receptor 1 (CB1R) from advillin+ peripheral sensory neurons eliminates the inhibitory effect of the peripheral CB1R antagonist JD5037 on voluntary ethanol intake (VEI). Thus, CB1R on Gpr65+ NGA projections to the mucosa of the gastrointestinal tract is essential for VEI. These findings also suggest a mutual interdependence of endocannabinoid and ghrelin signaling in controlling VEI via a gut-brain axis."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Gastrointestinal Disorder • Psychiatry • HOXB6 • PHOX2B

Targeting CB1R Rewires Ca2+-Dependent Mitophagy to Promote Nerve Regeneration. (PubMed, Theranostics) - "Targeting CB1R facilitates Ca2+ influx, enhances mitophagy via the PINK1/Parkin pathway, and promotes nerve regeneration. These findings identify CB1R as a viable therapeutic target and support the translational potential of JD5037 for nerve injury treatment."

Journal

Diet-dependent modulation of energy balance by CB1 signaling in peripheral sensory neurons. (PubMed, iScience) - "In this study, we show that rimonabant (Rim), a selective non-restricted CB1 antagonist, induces substantial weight loss across multiple diet groups, although reduced food intake occurred only in the high-fat (HF) diet group. Mice lacking CB1 in sensory neurons (Nav1.8Cre/CB1flox/flox) showed reduced diet-induced weight gain and diminished metabolic response to JD5037, a peripherally restricted CB1 antagonist. These findings emphasize the importance of CB1 signaling in sensory neurons as a key mechanism regulating energy homeostasis."

Journal • NAV1

Targeting the Endocannabinoid System to Suppress mTORC1 Hyperactivation in TSC-associated Kidney Disease. (PubMed, Am J Physiol Renal Physiol) - "Treatment with the peripheral CB1R antagonist JD5037 significantly reduced mTORC1 activity and c-Myc expression in cultured cells and ex vivo kidney organ cultures. These findings identified CB1R as a potential therapeutic target, linking endocannabinoid dysregulation to TSC kidney pathology."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease • MYC • TSC1

CB1 SIGNALING IN GUT SENSORY NEURONS: RECOGNIZING NOVEL MECHANISMS OF APPETITE AND ENERGY CONTROL (DDW 2025) - "CB1 was highly expressed in both spinal and vagal afferent neurons as evidenced by CB1 staining within celiac, nodose, and dorsal root ganglia in C57Blk/6J mice (Fig1). We administered a non-selective CB1 antagonist (SR14146A), and a peripherally restricted CB1 antagonist (JD5037) to Nav1.8-CB1 knockout mice, observing the distinct impacts on energy regulation. We found that both (SR14146A) and (JD5037) had a similar weight loss and food intake reduction response in Nav1.8-CB1 +/+ male mice, interestingly the reduction in food intake was lost when (JD5037) was administered to Nav1.8-CB1 -/- ."

Genetic Disorders • Obesity • LEP • NAV1

Maladaptive Peripheral Ketogenesis in Schwann Cells Mediated by CB1R Contributes to Diabetic Neuropathy. (PubMed, Adv Sci (Weinh)) - "Moreover, this metabolic reprogramming can be induced pharmacologically using JD5037, a peripheral CB1R blocker. These findings revealed a new metabolic mechanism underlying DPN, and promoted CB1R as a promising therapeutic target for DPN."

Journal • Diabetes • Diabetic Neuropathy • Metabolic Disorders • Pain • Type 1 Diabetes Mellitus • HMGCS2

Peripherally Restricted CB1 Receptor Inverse Agonist JD5037 Treatment Exacerbates Liver Injury in MDR2-Deficient Mice. (PubMed, Cells) - "In summary, our study reveals the exacerbating effect of JD5037 on liver fibrosis in genetically MDR2-deficient mice. These findings underscore the need for caution in the use of peripherally restricted CB1R inverse agonists for liver fibrosis treatment, particularly in cases of dysfunctional hepatic phospholipid transporter."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • ABCB4

Pharmaceutical targeting of the cannabinoid type 1 receptor impacts the crosstalk between immune cells and islets to reduce insulitis in humans. (PubMed, Diabetologia) - "These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor."

Immune cell • Journal • Diabetes • Immunology • Inflammation • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • ATF6 • CD4 • CNR1 • IFNG • IL1B • TNFA

Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner. (PubMed, Cardiovasc Res) - "Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • CNR1 • ER

The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice. (PubMed, Biol Res) - "Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice."

Journal • Preclinical • Genetic Disorders • Metabolic Disorders • Obesity • AMPK

Effects of the peripheral CB receptor antagonist JD5037 in mono- and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension. (PubMed, Front Pharmacol) - "In conclusion, monotherapy with JD5037 does not markedly influence the PH-related changes. However, polytherapy with metformin tends to be more efficient than any of these compounds alone."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Peripheral Cannabinoid-1 Receptor Blockade Ameliorates Cystitis Severity. (PubMed, Cannabis Cannabinoid Res) - "Materials and To this end, we used the cyclophosphamide (CYP; 300 mg/kg, intraperitoneal)-induced cystitis model of bladder dysfunction, in which 12-week-old, female C57BL/6 mice were treated with the peripherally restricted CBR antagonist, JD5037 (3 mg/kg), or vehicle for three consecutive days. These effects were associated with the ability of JD5037 to reduce CYP-induced inflammatory response, manifested by a reduction in levels of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα), in the bladder and serum. Collectively, our results highlight the therapeutic relevance of peripheral CBR blockade in ameliorating CYP-induced cystitis; they may further support the preclinical development and clinical use of peripherally restricted CBR antagonism for treatment of LUTSs."

Journal • Inflammation • Oncology • Urology • TNFA

Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia. (PubMed, Molecules) - "The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia."

Journal • Hepatology • Immunology • Inflammation • MRI

[VIRTUAL] Peripheral CB1 Inverse Agonism Improves Metabolism in DIO Mice Independent of Hepatic FGF21 (ADA 2021) - "Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in hFGF21 -/- mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB 1 R blockade by inverse agonist in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21."

Late-breaking abstract • Preclinical • Metabolic Disorders • Obesity • FGF21 • FGFR1

Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms. (PubMed, Diabetes) - "(R)-MRI-1867, the CB1R-inactive stereoisomer which retains iNOS inhibitory activity and JD-5037, a peripherally-restricted CB1R antagonist were used to assess the relative contribution of the two targets to the effects of (S)-MRI-1867...The decrease in VLDL secretion could be attributed to CB1R blockade while the reduction of PCSK9 levels and the related increase in LDLR resulted from iNOS inhibition via a mTORC1-dependent mechanism. In conclusion, this approach based on the concomitant inhibition of CB1R and iNOS represents a promising therapeutic strategy for the treatment of dyslipidemia."

Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • MRI

[VIRTUAL] Peripheral CB1R Blocker Improves Metabolism in Diet Induced Obese Mice Independent of Hepatic FGF21 (ENDO-I 2020) - "Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in FGF21-LKO mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB1R blockade in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21."

Preclinical • Genetic Disorders • Obesity • FGF • FGFR1

Cannabinoid-1 Receptor Antagonism Improves Glycemic Control and Increases Energy Expenditure via Sirt1/mTORC2 and AMPK Signaling. (PubMed, Hepatology) - "Feeding C57BL/6J mice a high-fat diet (HFD) inhibited hepatic Sirt1/mTORC2/Akt signaling, and the inhibition was reversed by rimonabant or JD5037 in wild-type but not liver-specific Sirt1 (Sirt1-LKO) mice, to levels observed in hepatocyte-specific CB R mice. In contrast, JD5037 treatment was equally effective in HFD-fed wild-type and Sirt1-LKO mice in reducing hepatic steatosis, increasing fatty acid β-oxidation and activating AMPK via LKB1, resulting in a similar increase in total energy expenditure in the two strains. peripheral CB R blockade in obese mice improves glycemic control via the hepatic Sirt1/mTORC2/Akt pathway, whereas it increases fatty acid oxidation via LKB1/AMPK signaling."

Journal • Diabetes • Genetic Disorders • Obesity

Preclinical toxicity evaluation of JD5037, a peripherally restricted CB receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. (PubMed, Regul Toxicol Pharmacol) - "Free access to food increased the plasma AUC by ∼4.5-fold at 20 mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150 mg/kg/day in rats, and 20 and 75 mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-level."

Journal • Preclinical • CNS Disorders • Dyslipidemia • Epilepsy • Genetic Disorders • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

Peripheral CB 1 R Blocker Improves Metabolism in Diet Induced Obese Mice Independent of Hepatic FGF21 (ENDO 2020) - "Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in FGF21-LKO mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB 1 R blockade in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21."

Preclinical • FGFR1