Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

  • Bioorg Med Chem. 2014 Dec 1;22(23):6694-6705. doi: 10.1016/j.bmc.2014.09.012.
Jani Korhonen  1 ,  Anne Kuusisto  1 ,  John van Bruchem  1 ,  Jayendra Z Patel  1 ,  Tuomo Laitinen  1 ,  Dina Navia-Paldanius  2 ,  Jarmo T Laitinen  2 ,  Juha R Savinainen  2 ,  Teija Parkkari  1 ,  Tapio J Nevalainen  3
Affiliations
  • 1. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
  • 2. School of Medicine, Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
  • 3. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland. Electronic address: [email protected].
PMID: 25282655 DOI: 10.1016/j.bmc.2014.09.012
Abstract

The key hydrolytic Enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol Lipase (MAGL), are potential targets for various therapeutic applications. In this paper, we present more extensively the results of our previous work on piperazine and piperidine carboxamides and carbamates as FAAH and MAGL inhibitors. The best compounds of these series function as potent and selective MAGL/FAAH inhibitors or as dual FAAH/MAGL inhibitors at nanomolar concentrations. This study revealed that MAGL inhibitors should comprise leaving-groups with a conjugate acid PKA of 8-10, while diverse leaving groups are tolerated for FAAH inhibitors.

Keywords
FAAH and MAGL inhibitors; Fatty acid amide hydrolase (FAAH); Monoacylglycerol lipase (MAGL).