• Andrea Duranti, Andrea Tontini, Francesca Antonietti, Federica Vacondio, Alessandro Fioni, Claudia Silva, Alessio Lodola, Silvia Rivara, Carlos Solorzano, Daniele Piomelli, Giorgio Tarzia, and Marco Mor.
• Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, I-61029 Urbino, Italy.
• J. Med. Chem. 2012 May 24;55(10):4824-36.

AbstractThe 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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