title: 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.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton Alberta T6G 2N8, Canada.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez
authors.forename: Khaled R A
authors.initials: KR
authors.lastname: Abdellatif
authors.forename: Morshed A
authors.initials: MA
authors.lastname: Chowdhury
authors.forename: Julie A
authors.initials: JA
authors.lastname: Reisz
authors.forename: Jenna F
authors.initials: JF
authors.lastname: DuMond
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004952:Esters; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D007052:Ibuprofen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009288:Naproxen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000378:metabolism*; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: C558521:2-(2-(1-(4-chlorobenzoyl)-2-methyl-5-methoxyl-1H-indoyl-3-yl)acetoxy)ethanesulfonyl hydroxamic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D004952:Esters; D006877:Hydroxamic Acids; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D011355:Prodrugs; D009288:Naproxen; D002351:Carrageenan; C039900:nitroxyl; D007052:Ibuprofen; D007213:Indomethacin