1. Academic Validation
  2. N-(2-oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: synthesis and structure-activity and structure-property relationships

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

  • J Med Chem. 2012 May 24;55(10):4824-36. doi: 10.1021/jm300349j.
Andrea Duranti 1 Andrea Tontini Francesca Antonietti Federica Vacondio Alessandro Fioni Claudia Silva Alessio Lodola Silvia Rivara Carlos Solorzano Daniele Piomelli Giorgio Tarzia Marco Mor
Affiliations

Affiliation

  • 1 Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, I-61029 Urbino, Italy.
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.

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