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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.

Journal of medicinal chemistry (2011-02-02)
Zhangjian Huang, Carlos A Velázquez, Khaled R A Abdellatif, Morshed A Chowdhury, Julie A Reisz, Jenna F DuMond, S Bruce King, Edward E Knaus
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ibuprofen, ≥98% (GC)
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Sigma-Aldrich
Naproxen, meets USP testing specifications
Supelco
Ibuprofen
Sigma-Aldrich
Indomethacin, meets USP testing specifications
Sigma-Aldrich
Ibuprofen, meets USP testing specifications
Sigma-Aldrich
(S)-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid, 98%
Supelco
Naproxen, VETRANAL®, analytical standard

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