Ethanesulfohydroxamic acid ester prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs): synthesis, nitric oxide and nitroxyl release, cyclooxygenase inhibition, anti-inflammatory, and ulcerogenicity index studies.

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Huang Z, Velazquez CA, Abdellatif KR, Chowdhury MA, Reisz JA, DuMond JF, King SB, Knaus EE

J Med Chem. 2011 Mar 10;54(5):1356-64. doi: 10.1021/jm101403g. Epub 2011 Jan 31.

PubMed ID

21280601 [ View in PubMed

]

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 mumol/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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ibuprofen	Prostaglandin G/H synthase 2	IC 50 (nM)	1400	N/A	N/A	Details
Indomethacin	Prostaglandin G/H synthase 2	IC 50 (nM)	6900	N/A	N/A	Details
Naproxen	Prostaglandin G/H synthase 2	IC 50 (nM)	12400	N/A	N/A	Details