| N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis, Structure-Activity and Structure-Property Relationships. | |
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MedLine Citation:
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PMID: 22515328 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The ß-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 investigated the structure-activity and structure-property relationships for a set of known and new ß-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, due to reduced intramolecular attack at the lactone ring. The introduction of a syn methyl at the ß-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. |
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Authors:
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Andrea Duranti; Andrea Tontini; Francesca Antonietti; Federica Vacondio; Alessandro Fioni; Claudia Silva; Alessio Lodola; Silvia Rivara; Carlos Solorzano; Daniele Piomelli; Giorgio Tarzia; Marco Mor |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-19 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: - ISSN: 1520-4804 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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