Evaluation of tetrahydropyridazine-based peripherally restricted dual inhibitors of CB1R and inducible nitric oxide synthase (iNOS) for treating metabolic syndrome disorders.

BACKGROUND AND PURPOSE: The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB). This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration. The efficacy of the compounds was assessed in rodent models of diet induced obesity and diabetes.

EXPERIMENTAL APPROACH: In this study, we employed a rational-design approach along with structure-based modeling to develop small-molecule CB1R antagonists that are peripherally acting. Pharmacological profiles of two racemic compounds PB19A and PB95 were evaluated in cannabinoid receptor binding studies, and functional [35S]-GTPγS assays. Further chiral separation of enantiomers allowed for the evaluation of respective eutomers in in vitro ADME studies along with in vivo pharmacokinetic and tissue distribution studies in mice. The results showed that the compounds are orally bioavailable and had negligible brain penetrance. The design features also incorporated putative amidine moieties which inhibit the pro-inflammatory enzyme; inducible nitric oxide synthase (iNOS). Both biochemical and in vitro cell-based assays showed the CB1R antagonists having iNOS inhibitor properties. In vivo CB1R functional antagonism was assessed by upper gastrointestinal motility assay. The efficacy of our CB1R antagonists was compared with brain penetrant ibipinabant in a diet-induced obesity mouse model, assessing effects on lipid metabolism biomarkers, food intake, body weight reduction, glucose tolerance and insulin resistance.

KEY RESULTS: Novel compounds PB19AE2 and PB95E2 were designed and evaluated as peripherally restricted CB1R antagonists. In high fat diet fed mice, these compounds improved metabolic parameters, modestly reduced food intake, and ameliorated hepatic lipid metabolism markers.

CONCLUSION AND IMPLICATIONS: Overall, PB19AE2 and PB95E2 are orally bioavailable, peripherally acting CB1 antagonists and their preliminary evaluation show promising potential in utilizing the pyridazine-based compounds for generating potent leads for treating obesity- associated disorders.