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Open Access Publications from the University of California

Synthesis, structure-activity, and structure-stability relationships of 2-substituted-n-(4-oxo-3-oxetanyl) n-acylethanolamine acid amidase (NAAA) inhibitors

  • Author(s): Vitale, R
  • Ottonello, G
  • Petracca, R
  • Bertozzi, SM
  • Ponzano, S
  • Armirotti, A
  • Berteotti, A
  • Dionisi, M
  • Cavalli, A
  • Piomelli, D
  • Bandiera, T
  • Bertozzi, F
  • et al.

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.

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