title: Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.
abstract: Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Migliore
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pontis
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Angel Luis
authors.initials: AL
authors.lastname: Fuentes de Arriba
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Esther
authors.initials: E
authors.lastname: Torrente
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Romeo
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Di Martino
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Lanfranco
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Ottonello
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Perrine
authors.initials: P
authors.lastname: Busquet
authors.affiliation: Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA 92697-4625, USA.
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.affiliation: Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego CA 92121, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia-Guzman
authors.affiliation: Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego CA 92121, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Heim
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.|Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA 92697-4625, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000284:Administration, Oral; D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004983:Ethanolamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D009829:Oleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010169:Palmitic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; D010169:Palmitic Acids; C488250:oleoylethanolamide; C005958:palmidrol; D000581:Amidohydrolases; C523108:NAAA protein, human
keywords: N-acylethanolamine acid amidase; cysteine hydrolase; fatty acylethanolamides; multiple sclerosis; neuroinflammation