title: NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect - why do we keep using it?
abstract: The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.
authors.affiliation: a Department of Chemistry , Islamia College Peshawar , Peshawar , Pakistan .|b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Nasir
authors.initials: N
authors.lastname: Ullah
authors.affiliation: c Center for Drug Discovery, China Pharmaceutical University, Nanjiang , Jiangsu , China , and.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Forough
authors.initials: F
authors.lastname: Sanaee
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rodriguez-Dimitrescu
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Fahad
authors.initials: F
authors.lastname: Aldawsari
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Fakhreddin
authors.initials: F
authors.lastname: Jamali
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Atul
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: d Department of Pharmacy , Sarhad University of Science and Information Technology , Peshawar , Pakistan.
authors.forename: Nazar Ul
authors.initials: NU
authors.lastname: Islam
authors.affiliation: b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton , Alberta , Canada .
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002264:Carboxylic Acids / Q000737:chemistry*; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids
keywords: Anti-inflammatory; NSAIDs; cyclooxygenase