A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation.
Pain states that arise from non-resolving inflammation, such as inflammatory bowel disease or arthritis, pose an unusually difficult challenge for therapy because of the complexity and heterogeneity of their underlying mechanisms. It has been suggested that key nodes linking interactive pathogenic pathways of non-resolving inflammation might offer novel targets for the treatment of inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclooxygenase (COX)-mediated production of pain- and inflammation-inducing prostanoids, are a common first-line treatment for this condition, but their use is limited by mechanism-based side effects. The endogenous levels of anandamide, an endocannabinoid mediator with analgesic and tissue-protective functions, are regulated by fatty acid amide hydrolase (FAAH). This review outlines the pharmacological and chemical rationale for the simultaneous inhibition of COX and FAAH activities with designed multitarget agents. Preclinical studies indicate that such agents may combine superior anti-inflammatory efficacy with reduced toxicity.
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163, Genoa, Italy.
Rita
R
Scarpelli
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163, Genoa, Italy.
Oscar
O
Sasso
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163, Genoa, Italy. daniele.piomelli@iit.it.|Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, 92697-4625, USA. daniele.piomelli@iit.it.
Daniele
D
Piomelli
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry / Q000627:therapeutic use; D002227:Carbazoles / Q000737:chemistry / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D010146:Pain / Q000188:drug therapy*; D010666:Phenylpropionates / Q000737:chemistry / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001713:Biphenyl Compounds; D002227:Carbazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D000099252:Fatty Acid Amide Hydrolases
drug design; enzymes; inflammation; multitarget inhibitors; pain; structure-activity relationships