Loratadine analogues as MAGL inhibitors

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50 = 46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50 = 7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50 = 1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2 = 6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.

Figure optionsDownload as PowerPoint slide