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Issue 2, 2019
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Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors

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Abstract

N-Acylethanolamine acid amidase (NAAA) is one of the key enzymes involved in the degradation of fatty acid ethanolamides (FAEs), especially for palmitoylethanolamide (PEA). Pharmacological blockage of NAAA restores PEA levels, providing therapeutic benefits in the management of inflammation and pain. In the current work, we showed the structure–activity relationship (SAR) studies for pyrrolidine amide derivatives as NAAA inhibitors. A series of aromatic replacements or substituents for the terminal phenyl group of pyrrolidine amides were examined. SAR data showed that small lipophilic 3-phenyl substituents were preferable for optimal potency. The conformationally flexible linkers increased the inhibitory potency of pyrrolidine amide derivatives but reduced their selectivity toward fatty acid amide hydrolase (FAAH). The conformationally restricted linkers did not enhance the inhibitor potency toward NAAA but improved the selectivity over FAAH. Several low micromolar potent NAAA inhibitors were developed, including 4g bearing a rigid 4-phenylcinnamoyl group. Dialysis and kinetic analysis suggested that 4g inhibited NAAA via a competitive and reversible mechanism. Furthermore, 4g showed high anti-inflammatory activities in lipopolysaccharide (LPS) induced acute lung injury (ALI) model, and this effect was blocked by pre-treatment with the PPAR-α antagonist MK886. We anticipate that 4g (E93) will enable a new agent to treat inflammation and related diseases.

Graphical abstract: Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors

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Publication details

The article was received on 30 Aug 2018, accepted on 14 Dec 2018 and first published on 18 Dec 2018


Article type: Research Article
DOI: 10.1039/C8MD00432C
Citation: Med. Chem. Commun., 2019,10, 252-262

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    Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors

    P. Zhou, L. Xiang, D. Zhao, J. Ren, Y. Qiu and Y. Li, Med. Chem. Commun., 2019, 10, 252
    DOI: 10.1039/C8MD00432C

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