Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB<sub>1</sub>R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis

Iyer, Malliga R.; Çınar, Reşat; Katz, Alexis; Gao, Michael C.; Erdélyi, Katalin; Jourdan, Tony; Coffey, Nathan J.; Pacher, Pál; Kunos, George

doi:10.1021/acs.jmedchem.6b01504

Cited by 36 publications

(49 citation statements)

References 37 publications

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“…In this regard, several of the conditions described above in which circulating endocannabinoids are elevated also result in inflammation, including acute bouts of exercise (Ruderman et al, 2006) and obesity (Marsland et al, 2010), data that support the possibility that there are connections between endocannabinoids and inflammation. Activation of CB1R signaling in the context of inflammation can be a contributing factor to fibrosis and other detrimental effects of chronic inflammation (Iyer et al, 2017). Circulating concentrations of AEA are elevated in patients with cirrhosis and their concentrations are positively correlated with negative indices of liver function (Caraceni et al, 2010).…”

Section: Circulating Endocannabinoids and Inflammationmentioning

confidence: 99%

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

Hillard

2017

Neuropsychopharmacol.

322

241

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The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder.

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Section: Circulating Endocannabinoids and Inflammationmentioning

confidence: 99%

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

Hillard

2017

Neuropsychopharmacol.

322

241

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“…This type of approach would benefit from the use of lower doses of the drugs, thus limiting possible side effects, while acting on different biological systems that participate in the regulation of energy balance, possibly leading to greater therapeutic success. For instance, a recent study by Kunos et al has characterized the effects of a hybrid inhibitor of peripheral CB 1 R and inducible nitric oxide synthase (iNOS) for the treatment of liver fibrosis (123,124). This orally bioavailable compound accumulates in the liver where it releases an iNOS inhibitor, providing the possible advantage of an organ-targeted action.…”

Section: The Ecs and Metabolic Disorders In Humansmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Simon

Cota

2017

European Journal of Endocrinology

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The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB 1 R and CB 2 R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance. Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain penetrant CB 1 R antagonists like rimonabant for obesity and metabolic disorders. Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment. Accordingly, peripherally restricted CB 1 R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models. Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB 1 R, the characterization of the structure of the human CB 1 R, and the likely involvement of CB 2 R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.

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“…Although not yet investigated as an antiobesity therapeutic, AM1710 is not brain penetrant [206], which is suggestive of a potential therapeutic that warrants further investigation. Recently, a dual target peripheral CB1 antagonist/iNOS inhibitor was reported to be effective in mitigating liver fibrosis, reducing bodyweight, hepatic steatosis and improving glucose tolerance in mice without inducing anxiety-like behavior [207,208]. A list of the emerging therapeutics is provided in Table 1.…”

Section: Development Of Peripheral Specific Cb Ligandsmentioning

confidence: 99%

Peripheral modulation of the endocannabinoid system in metabolic disease

Shrestha

Cuffe

Hutchinson

et al. 2018

Drug Discovery Today

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Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity.

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Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB₁R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis

Cited by 36 publications

References 37 publications

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Peripheral modulation of the endocannabinoid system in metabolic disease

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Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis

Cited by 36 publications

References 37 publications

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Peripheral modulation of the endocannabinoid system in metabolic disease

Contact Info

Product

Resources

About

Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB₁R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis