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 (IC50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis, Structure–Activity and Structure–Property Relationships / A. Duranti; A. Tontini; F. Antonietti; F. Vacondio; A. Fioni; C. Silva; A. Lodola; S. Rivara; C. Solorzano; D. Piomelli; G. Tarzia; M. Mor. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 55(2012), pp. 4824-4836. [10.1021/jm300349j]
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