title: Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity.
abstract: Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50= 72 microM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50= 7 microM).
authors.affiliation: Centre for Synthesis and Chemical Biology, Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Jean
authors.initials: J
authors.lastname: Lee
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chubb
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Moman
authors.forename: Brian M
authors.initials: BM
authors.lastname: McLoughlin
authors.forename: Caroline T
authors.initials: CT
authors.lastname: Sharkey
authors.forename: John G
authors.initials: JG
authors.lastname: Kelly
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Nolan
authors.forename: Marc
authors.initials: M
authors.lastname: Devocelle
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Fitzgerald
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010544:Peroxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D062367:ortho-Aminobenzoates; C413218:anthranilic hydroxamic acid; D010544:Peroxidases; D011451:Prostaglandin-Endoperoxide Synthases