Design and Synthesis of Cannabinoid Receptor 1 Antagonists for Peripheral Selectivity

Abstract

Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease and diabetes. Recently, development of several CB1 antagonists was halted due to adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.

Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

“…Compounds that demonstrated K e < 100 nM were further characterized using competitive radioligand displacement of [ 3 H]CP55940 at CB1 and CB2 overexpressing membrane preparations as described previously. 13 Displacement data were quantified and expressed as an equilibrium dissociation constant ( K i ) value at each receptor. Potent and selective compounds were progressed into an in vitro model of brain penetration in monolayers of MDCK-mdr1cells as described previously.…”

“…13 These results along with our interest in CB1 antagonists that possess a purine core, like 2 , moved us to make purine 9 . Purine 9 is a potent ( K e = 9 nM) and selective (CB2/CB1 selectivity ratio ∼ 3077) hybrid of 2 and 8 with a TPSA of 90.…”

“…13 While this compound was promising, having a brain to plasma ratio of less than 4% in a simple pharmacokinetic experiment, oral absorption of this compound was less than optimal. 13 …”

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

“…36,37 Compounds were added to the apical side at a concentration of 10 μ M in a transport buffer comprising 1× Hank’s balanced salt solution, 25 mM d -glucose, and buffered with HEPES to pH 7.4. Samples were incubated for 1 h at 37 °C and carefully collected from both the apical and basal side of the filters.…”

Synthesis and Structure–Activity Relationship Studies ofO-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

“…Indeed, synthetic efforts aimed at creating CB 1 receptor agonists and antagonists with restricted access to the CNS have been reported. 9,10,11,12 In those studies, the main strategies adopted to limit access of compounds of interest to the CNS were either to increase the compounds’ topological polar surface area (TPSA) 11 or to exploit the recognition by drug transporters present in the blood-brain barrier (BBB). 12 …”