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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, Andrea
  • Tontini, Andrea
  • Antonietti, Francesca
  • Vacondio, Federica
  • Fioni, Alessandro
  • Silva, Claudia
  • Lodola, Alessio
  • Rivara, Silvia
  • Solorzano, Carlos
  • Piomelli, Daniele
  • Tarzia, Giorgio
  • Mor, Marco
  • et al.

Published Web Location Commons 'BY' version 4.0 license

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.

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