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Ethanesulfohydroxamic Acid Ester Prodrugs of Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Synthesis, Nitric oxide and Nitroxyl Release, Cyclooxygenase Inhibition, Anti-inflammatory, and Ulcerogenicity Index Studies.
MedLine Citation:
PMID:  21280601     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S)-naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH(2)CH(2)SO(2)NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 μmol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO.
Authors:
Zhangjian Huang; Carlos A Velázquez; Khaled R A Abdellatif; Morshed A Chowdhury; Julie A Reisz; Jenna F Dumond; S Bruce King; Edward E Knaus
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-1-31
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-2-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton Alberta T6G 2N8, Canada.
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