2. Academic Validation
  3. Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis

Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis

  • Angew Chem Int Ed Engl. 2016 Sep 5;55(37):11193-11197. doi: 10.1002/anie.201603746.
Marco Migliore Dr  # 1,  Silvia Pontis Dr  # 1,  Angel Luis Fuentes de Arriba 1,  Natalia Realini 1,  Esther Torrente 1,  Andrea Armirotti 1,  Elisa Romeo 1,  Simona Di Martino 1,  Debora Russo 1,  Daniela Pizzirani 1,  Maria Summa 1,  Massimiliano Lanfranco 1,  Giuliana Ottonello 1,  Perrine Busquet 1,  Kwang-Mook Jung 2,  Miguel Garcia-Guzman 3,  Roger Heim 3,  Rita Scarpelli 1,  Daniele Piomelli 1 2
Affiliations

Affiliations

  • 1 Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
  • 2 Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA 92697-4625, USA.
  • 3 Anteana Therapeutics, 11189 Sorrento Valley Road, Suite 104, San Diego CA 92121, USA.
  • # Contributed equally.
PMID: 27404798 DOI: 10.1002/anie.201603746
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.

Keywords

N-acylethanolamine acid amidase; cysteine hydrolase; fatty acylethanolamides; multiple sclerosis; neuroinflammation.

Figures
Products