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

Jani Korhonen; Anne Kuusisto; John van Bruchem; Jayendra Z Patel; Tuomo Laitinen; Dina Navia-Paldanius; Jarmo T Laitinen; Juha R Savinainen; Teija Parkkari; Tapio J Nevalainen

doi:10.1016/j.bmc.2014.09.012

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. Epub 2014 Sep 16.

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: tapio.nevalainen@uef.fi.

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology
Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / metabolism
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Models, Molecular
Molecular Structure
Monoacylglycerol Lipases / antagonists & inhibitors*
Monoacylglycerol Lipases / metabolism
Piperazine
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology
Structure-Activity Relationship

Substances

Amides
Carbamates
Enzyme Inhibitors
Piperazines
Piperidines
Piperazine
piperidine
Monoacylglycerol Lipases
Amidohydrolases
fatty-acid amide hydrolase