Loratadine analogues as MAGL inhibitors

  • Bioorg Med Chem Lett. 2015 Apr 1;25(7):1436-42. doi: 10.1016/j.bmcl.2015.02.037.
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
  • 1. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. Electronic address: [email protected].
  • 2. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
  • 3. School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
  • 4. Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Lodz, 90-151 Lodz, Poland.
PMID: 25752982 DOI: 10.1016/j.bmcl.2015.02.037
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.
Products