title: Piperazine and piperidine carboxamides and carbamates as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
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.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Korhonen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Kuusisto
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: John
authors.initials: J
authors.lastname: van Bruchem
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Jayendra Z
authors.initials: JZ
authors.lastname: Patel
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland.
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-7021 Kuopio, Finland. Electronic address: tapio.nevalainen@uef.fi.
authors.forename: Tapio J
authors.initials: TJ
authors.lastname: Nevalainen
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D000077489:Piperazine; D010879:Piperazines; D010880:Piperidines; D000099252:Fatty Acid Amide Hydrolases; C032727:piperidine
keywords: FAAH and MAGL inhibitors; Fatty acid amide hydrolase (FAAH); Monoacylglycerol lipase (MAGL)