Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.
Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.
Onnis
Valentina
V
Department of Toxicology, Unit of Medicinal Chemistry, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy. vonnis@unica.it
Congiu
Cenzo
C
Björklund
Emmelie
E
Hempel
Franziska
F
Söderström
Emma
E
Fowler
Christopher J
CJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D001565:Benzoates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide