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N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships

  • Author(s): Duranti, A
  • Tontini, A
  • Antonietti, F
  • Vacondio, F
  • Fioni, A
  • Silva, C
  • Lodola, A
  • Rivara, S
  • Solorzano, C
  • Piomelli, D
  • Tarzia, G
  • Mor, M
  • et al.

Published Web Location

https://doi.org/10.1021/jm300349jCreative Commons Attribution 4.0 International Public License
Abstract

The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC 50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications. © 2012 American Chemical Society.

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