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

Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis. Regul Toxicol Pharmacol. 2019 Sep 30;:104483 Authors: Kale VP, Gibbs S, Taylor JA, Zmarowski A, Novak J, Patton K, Sparrow B, Gorospe J, Anand S, Cinar R, Kunos G, Chorvat RJ, Terse PS Abstract 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 34-days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28-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 kin...
Source: Regulatory Toxicology and Pharmacology : RTP - Category: Toxicology Authors: Tags: Regul Toxicol Pharmacol Source Type: research