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. 2015 Apr 1;25(7):1436-42.
doi: 10.1016/j.bmcl.2015.02.037. Epub 2015 Feb 24.

Loratadine analogues as MAGL inhibitors

Jayendra Z Patel  1 , Stephen Ahenkorah  2 , Miia Vaara  3 , Marek Staszewski  4 , Yahaya Adams  2 , Tuomo Laitinen  2 , Dina Navia-Paldanius  3 , Teija Parkkari  2 , Juha R Savinainen  3 , Krzysztof Walczyński  4 , Jarmo T Laitinen  3 , Tapio J Nevalainen  2
Affiliations

Loratadine analogues as MAGL inhibitors

Jayendra Z Patel et al. Bioorg Med Chem Lett. .

Abstract

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.

Keywords: 2-Arachidonoyl glycerol; Fatty acid amide hydrolase; Loratadine; Monoacylglycerol lipase; α/β hydrolase-6.

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