Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis

Kale, Vijay P.; Gibbs, Seth; Taylor, John A.; Zmarowski, Amy; Novak, Joseph P.; Patton, Kristen K.; Sparrow, Barney; Gorospe, Jenni; Anand, S. Satheesh; Çınar, Reşat; Kunos, George; Chorvat, Robert J.; Terse, Pramod

doi:10.1016/j.yrtph.2019.104483

Cited by 21 publications

(16 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Phase I trials showed desired weight gain [340]. CRB-4001, a peripheral CB1 inverse agonist is waiting for phase I trial as a potential drug for nonalcoholic steatohepatitis [341,342].…”

Section: Approved Drugs and Clinical Trialsmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

View full text Add to dashboard Cite

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.

show abstract

“…Phase I trials showed desired weight gain [340]. CRB-4001, a peripheral CB1 inverse agonist is waiting for phase I trial as a potential drug for nonalcoholic steatohepatitis [341,342].…”

Section: Approved Drugs and Clinical Trialsmentioning

confidence: 99%

A Guide to Targeting the Endocannabinoid System in Drug Design

Stasiulewicz

Znajdek

Grudzień

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…In addition to metabolic disorders, preclinical research suggests peripherally restricted antagonists have beneficial effects on kidney diseases [92,93], liver fibrosis and steatosis [94][95][96], pulmonary fibrosis [97,98], and alcoholism [99] (see Table 2). In some cases, some third-generation compounds have been designed to inhibit more than one molecular target.…”

Section: Peripherally Restricted Cb 1 Antagonistsmentioning

confidence: 99%

“…JD5037 is a peripherally restricted CB 1 inverse agonist developed by Jenrin Discovery and licensed to Corbus Pharmaceuticals (now CRB-4001), which is due to begin phase 1 testing in the first half of 2022 (https://www.corbuspharma.com/our-pipeline/ endocannabinoid-system (accessed on 10 September 2021)). [85,105] Prader-Willi syndrome [88] Chronic kidney disease [101] Diabetic nephropathy [93] Alcoholic liver steatosis [94] Alcoholism [99,100] Non-alcoholic liver steatosis [96] Obesity-related liver steatosis [95] Liver fibrosis [102] Pulmonary fibrogenesis [97,98] Skin fibrosis [103] Inflammatory pain [106,107] Neuropathic pain [107,108] Bone cancer pain [109] Chemotherapy-induced pain [110] Migraine and medication overuse headache [111] Spasticity in multiple sclerosis [112] Gastrointestinal motility in colitis [42,43] Anticipatory nausea [113] Cardiac disease [114] Neuropathic pain [115] Chemotherapy-induced neuropathy [116] Inflammatory pain [115,117,118] Diabetic neuropathy [119] Visceral pain [115] Migraine [120,121] Anticipatory nausea [113] Cystitis [122] Bladder overactivity [123] Gastric lesions [118] Clinical research INV-101 in Prader-Willi syndrome (PWS) and non-alcoholic steatohepatitis (NCT04531150) (Inversago Pharma) TM38837 in healthy subjects [104] (7TM Pharma) GFB-024 in diabetic nephropathy (Goldfinch Bio, NCT04880291) AZ...…”

Section: Peripherally Restricted Cb 1 Antagonistsmentioning

confidence: 99%

The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

O’Sullivan¹,

Yates²,

Porter

2021

Molecules

View full text Add to dashboard Cite

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut–brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.

show abstract

“…On the other hand, JD5037 was approved by the FDA as an investigational new drug [165]. Studies proved its preclinical efficacy for Prader-Willi syndrome and renal impairment induced by diabetes [168], but stereotypical neurobehaviors were observed in male and female rats after its administration [169]. Another CB1 inverse agonist compound (which still calls for investigation but has shown promising results for the treatment of obesity while maintaining low plasma/brain concentration) is Compound2p, whose administration showed enhanced glucose absorption in obese animals [170].…”

Section: Endocannabinoid System As a Pharmacological Target For Obesity And Food Addictionmentioning

confidence: 99%

Obesity as a Condition Determined by Food Addiction: Should Brain Endocannabinoid System Alterations Be the Cause and Its Modulation the Solution?

et al. 2021

View full text Add to dashboard Cite

Obesity is a complex disorder, and the number of people affected is growing every day. In recent years, research has confirmed the hypothesis that food addiction is a determining factor in obesity. Food addiction is a behavioral disorder characterized by disruptions in the reward system in response to hedonic eating. The endocannabinoid system (ECS) plays an important role in the central and peripheral control of food intake and reward-related behaviors. Moreover, both obesity and food addiction have been linked to impairments in the ECS function in various brain regions integrating peripheral metabolic signals and modulating appetite. For these reasons, targeting the ECS could be a valid pharmacological therapy for these pathologies. However, targeting the cannabinoid receptors with inverse agonists failed when used in clinical contexts as a consequence of the induction of affective disorders. In this context, new classes of drugs acting either on CB1 and/or CB2 receptors or on synthetic and degradation enzymes of endogenous cannabinoids are being studied. However, further investigation is necessary to find safe and effective treatments that can exert anti-obesity effects, normalizing reward-related behaviors without causing important adverse mood effects.

show abstract

Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis

Cited by 21 publications

References 23 publications

A Guide to Targeting the Endocannabinoid System in Drug Design

A Guide to Targeting the Endocannabinoid System in Drug Design

The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

Obesity as a Condition Determined by Food Addiction: Should Brain Endocannabinoid System Alterations Be the Cause and Its Modulation the Solution?

Contact Info

Product

Resources

About