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

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 5 Pg. 1356-64 (Mar 10 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21280601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(1-(4-chlorobenzoyl)-2-methyl-5-methoxyl-1H-indoyl-3-yl)acetoxy)ethanesulfonyl hydroxamic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase Inhibitors
• Esters
• Hydroxamic Acids
• Nitric Oxide Donors
• Nitrogen Oxides
• Prodrugs
• Naproxen
• Carrageenan
• nitroxyl
• Ibuprofen
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects, chemical synthesis, pharmacology)
• Carrageenan
• Cyclooxygenase Inhibitors (adverse effects, chemical synthesis, pharmacology)
• Edema (chemically induced, drug therapy)
• Esters
• Gastric Mucosa (drug effects, pathology)
• Humans
• Hydroxamic Acids (adverse effects, chemical synthesis, pharmacology)
• Ibuprofen (adverse effects, analogs & derivatives, chemical synthesis, pharmacology)
• Indomethacin (adverse effects, analogs & derivatives, chemical synthesis, pharmacology)
• Male
• Naproxen (adverse effects, analogs & derivatives, chemical synthesis, pharmacology)
• Nitric Oxide Donors (adverse effects, chemical synthesis, pharmacology)
• Nitrogen Oxides (metabolism)
• Prodrugs (adverse effects, chemical synthesis, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Stereoisomerism
• Stomach Ulcer (chemically induced, pathology)
• Structure-Activity Relationship