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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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