title: Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage.
abstract: The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Sasso
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Migliore
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Damien
authors.initials: D
authors.lastname: Habrant
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Albani
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Moreno-Sanz
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: *Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; and Departments of Anatomy and Neurobiology and Pharmacology and Biological Chemistry, University of California-Irvine, Irvine, California, USA piomelli@uci.edu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D048448:Phenylcarbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010666:Phenylpropionates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D048448:Phenylcarbamates; D010666:Phenylpropionates; D000099252:Fatty Acid Amide Hydrolases; C000600450:ARN2508
keywords: anandamide; cannabinoid receptor; inflammatory bowel disease; multitarget inhibitors