6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB₁) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity

Abstract

A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB 1 R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure−activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB 1 R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.

Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome

“…With a considerably lower exposure in the brain, Compound D4, developed by 7TM Pharma, induced pronounced weight reduction in a dose-dependent manner in obese mice in comparison with rimonabant [146]. Although designed to be a P-glycoprotein (P-gp) substrate in order to decrease its brain penetration, Compound 6a, developed by Janssen Research & Development, accumulated in the brain following chronic administration, suggesting that its in vivo metabolic efficacy cannot exclude blocking central CB 1 Rs [147]. Compound 2p, which originated from the brain-penetrant CB 1 R inverse agonist program of the same group, reduced glucose levels without centrally mediated behavioral effects and a reduction in food intake or body weight [148].…”

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

“…An important factor supporting THCV use in therapy could also be its antipsychotic effect [180]. Other compounds with same pharmacodynamics, i.e., able to influence feeding behaviour, which still require further research include: NESS06SM [181], SM-11 [182], PIMSR [183], BAR-1 [184], Compound10q [185], Compound2c [186], Com-pound5 [172], Compound13 [165], Compound6a [187], and CompoundD4 [188]. These were designed to have low penetration in the brain, except for Compound6a, whose chronic administration caused accumulation in the brain [187].…”

“…Other compounds with same pharmacodynamics, i.e., able to influence feeding behaviour, which still require further research include: NESS06SM [181], SM-11 [182], PIMSR [183], BAR-1 [184], Compound10q [185], Compound2c [186], Com-pound5 [172], Compound13 [165], Compound6a [187], and CompoundD4 [188]. These were designed to have low penetration in the brain, except for Compound6a, whose chronic administration caused accumulation in the brain [187]. On the other hand, clinical studies demonstrated decreased body weight and a safe administration profile for two other CB1 antagonists: AVE-1625 [174] and SLV-319 [189].…”

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

“…MRI-1867 is a low brain penetrating CB1 inverse agonist developed for the treatment of liver fibrosis, and DIO mice treated with MRI-1867 for 28 days experienced significant reductions in body weight and food intake, and increased energy expenditure [ 68 , 170 ]. Other similar compounds include Compound 6a, BMS-725519, BMS-811064, and BMS-812204 [ 73 , 171 ]. All of these novel compounds require further investigation.…”