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

JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose l...

Full description

Saved in:
Bibliographic Details
Published in:Regulatory toxicology and pharmacology 2019-12, Vol.109, p.104483-104483, Article 104483
Main Authors: Kale, Vijay Pralhad, Gibbs, Seth, Taylor, John A., Zmarowski, Amy, Novak, Joseph, Patton, Kristin, Sparrow, Barney, Gorospe, Jenni, Anand, Satheesh, Cinar, Resat, Kunos, George, Chorvat, Robert J., Terse, Pramod S.
Format: Article
Language:English
Subjects:
Inverse agonist
JD5037
Nonalcoholic steatohepatitis (NASH)
Obesity
Peripheral cannabinoid receptor 1 (CB1R)
Preclinical safety
Toxicity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40 mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75 mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. 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-levels (NOAELs). •Preclinical toxicology studies of JD5037, a peripheral CB1R inverse agonist, were conducted in rats and dogs.•JD5037 exhibited non-linear kinetics in both the species.•Fed state increased plasma exposure of JD5037 in dogs by 4.4–4.6-fold compared to fasting state.•NOAEL in rats was 150 mg/kg/day, while in male and female dogs it was 20 mg/kg/day and 75 mg/kg/day, respectively.
ISSN:0273-2300
1096-0295
1096-0295
DOI:10.1016/j.yrtph.2019.104483