1374666-79-1Relevant academic research and scientific papers
N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships
Duranti, Andrea,Tontini, Andrea,Antonietti, Francesca,Vacondio, Federica,Fioni, Alessandro,Silva, Claudia,Lodola, Alessio,Rivara, Silvia,Solorzano, Carlos,Piomelli, Daniele,Tarzia, Giorgio,Mor, Marco
, p. 4824 - 4836 (2012/07/03)
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.
