Academic Journal
Design and synthesis of cyanamides as potent and selective N-acylethanolamine acid amidase inhibitors.
| Τίτλος: | Design and synthesis of cyanamides as potent and selective N-acylethanolamine acid amidase inhibitors. |
|---|---|
| Συγγραφείς: | Malamas MS; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States. Electronic address: m.malamas@northeastern.edu., Farah SI; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Lamani M; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Pelekoudas DN; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Perry NT; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Rajarshi G; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Miyabe CY; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Chandrashekhar H; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., West J; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Pavlopoulos S; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States., Makriyannis A; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, United States. |
| Πηγή: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jan 01; Vol. 28 (1), pp. 115195. Date of Electronic Publication: 2019 Nov 11. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford : New York : Pergamon Press, c1993- |
| Ιατρικοί όροι (MeSH): | Drug Design*, Amidohydrolases/*antagonists & inhibitors , Cyanamide/*pharmacology , Enzyme Inhibitors/*pharmacology, Amidohydrolases/metabolism ; Cyanamide/chemical synthesis ; Cyanamide/chemistry ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Animals ; Dose-Response Relationship, Drug ; Mice ; Models, Molecular ; Molecular Structure ; Rats ; Structure-Activity Relationship |
| Περίληψη: | N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed >100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway,1-4 and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties.5-8 Our ligand design strategy followed a traditional structure-activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t (Copyright © 2019 Elsevier Ltd. All rights reserved.) |
| Grant Information: | R21 DA037575 United States DA NIDA NIH HHS; R33 DA037575 United States DA NIDA NIH HHS; R01 DA003801 United States DA NIDA NIH HHS |
| Contributed Indexing: | Keywords: Anandamide (AEA); Antinociception; CB1, CB2 cannabinoid receptors; Fatty acid amide hydrolase (FAAH); Inflammation; Monoacylglycerol lipase (MGL); N-acylethanolamine acid amidase (NAAA); N-palmitoylethanolamide (PEA); Nuclear peroxisome proliferator-activated receptor-α (PPAR-α) |
| Substance Nomenclature: | 0 (Enzyme Inhibitors) 420-04-2 (Cyanamide) EC 3.5.- (Amidohydrolases) EC 3.5.1.- (NAAA protein, human) |
| Entry Date(s): | Date Created: 20191126 Date Completed: 20210127 Latest Revision: 20260307 |
| Update Code: | 20260307 |
| DOI: | 10.1016/j.bmc.2019.115195 |
| PMID: | 31761726 |
| Βάση Δεδομένων: | MEDLINE |
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