N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure鈥揂ctivity and Structure鈥揚roperty Relationships

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• 作者：Andrea Duranti ; Andrea Tontini ; Francesca Antonietti ; Federica Vacondio ; Alessandro Fioni ; Claudia Silva ; Alessio Lodola ; Silvia Rivara ; Carlos Solorzano ; Daniele Piomelli ; Giorgio Tarzia ; Marco Mor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4824-4836
• 全文大小：467K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

The 尾-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鈥揳ctivity and structure鈥損roperty relationships for a set of known and new 尾-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 尾-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.