Academic Journal
Design and Structure-Activity Relationships of Isothiocyanates as Potent and Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibitors.
| Τίτλος: | Design and Structure-Activity Relationships of Isothiocyanates as Potent and Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibitors. |
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| Συγγραφείς: | Malamas MS; Northeastern University, Boston, Massachusetts 02115, United States., Pavlopoulos S; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Alapafuja SO; MAK Scientific LLC, 151 South Bedford Street, Burlington, Massachusetts 01803, United States., Farah SI; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Zvonok A; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Mohammad KA; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., West J; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Perry NT; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Pelekoudas DN; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Rajarshi G; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Shields C; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Chandrashekhar H; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Wood J; Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, United States., Makriyannis A; Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States. |
| Πηγή: | Journal of medicinal chemistry [J Med Chem] 2021 May 13; Vol. 64 (9), pp. 5956-5972. Date of Electronic Publication: 2021 Apr 26. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| Ιατρικοί όροι (MeSH): | Drug Design*, Amidohydrolases/*antagonists & inhibitors , Enzyme Inhibitors/*chemistry , Enzyme Inhibitors/*pharmacology , Isothiocyanates/*chemistry , Isothiocyanates/*pharmacology, Amidohydrolases/metabolism ; Drug Stability ; Humans ; Hydrolysis ; Structure-Activity Relationship |
| Περίληψη: | N-Acylethanolamines are signaling lipid molecules implicated in pathophysiological conditions associated with inflammation and pain. N-Acylethanolamine acid amidase (NAAA) favorably hydrolyzes lipid palmitoylethanolamide, which plays a key role in the regulation of inflammatory and pain processes. The synthesis and structure-activity relationship studies encompassing the isothiocyanate pharmacophore have produced potent low nanomolar inhibitors for hNAAA, while exhibiting high selectivity (>100-fold) against other serine hydrolases and cysteine peptidases. We have followed a target-based structure-activity relationship approach, supported by computational methods and known cocrystals of hNAAA. We have identified systemically active inhibitors with good plasma stability (t |
| Grant Information: | R21 DA037575 United States DA NIDA NIH HHS; R33 DA037575 United States DA NIDA NIH HHS; R43 DK104636 United States DK NIDDK NIH HHS; R44 DK104636 United States DK NIDDK NIH HHS |
| Substance Nomenclature: | 0 (Enzyme Inhibitors) 0 (Isothiocyanates) 3129-90-6 (isothiocyanic acid) EC 3.5.- (Amidohydrolases) |
| Entry Date(s): | Date Created: 20210426 Date Completed: 20210614 Latest Revision: 20260919 |
| Update Code: | 20260919 |
| DOI: | 10.1021/acs.jmedchem.1c00076 |
| PMID: | 33900772 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.1c00076 |