| Autor: |
Vitale, R, Ottonello, G, Petracca, R, Bertozzi, SM, Ponzano, S, Armirotti, A, Berteotti, A, Dionisi, M, Cavalli, A, Piomelli, D, Bandiera, T, Bertozzi, F |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Zdroj: |
Vitale, R; Ottonello, G; Petracca, R; Bertozzi, SM; Ponzano, S; Armirotti, A; et al.(2014). Synthesis, structure-activity, and structure-stability relationships of 2-substituted-n-(4-oxo-3-oxetanyl) n-acylethanolamine acid amidase (NAAA) inhibitors. ChemMedChem, 9(2), 323-336. doi: 10.1002/cmdc.201300416. UC Berkeley: Retrieved from: http://www.escholarship.org/uc/item/8qx6802s |
| DOI: |
10.1002/cmdc.201300416. |
| Popis: |
N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator-activated receptora (PPAR-a). Compounds that feature an a-amino-b-lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti-inflammatory effects that are mediated through FAE-dependent activation of PPAR-a. We synthesized and tested a series of racemic, diastereomerically pure b-substituted a-amino-b-lactones, as either carbamate or amide derivatives, investigating the structure-activity and structure-stability relationships (SAR and SSR) following changes in b-substituent size, relative stereochemistry at the a- and b-positions, and a-amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the b-position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. © 2014 Wiley-VCH Verlag GmbH and Co. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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