title: Oxicams, a class of nonsteroidal anti-inflammatory drugs and beyond.
abstract: Oxicams are a class of nonsteroidal anti-inflammatory drugs (NSAIDs) structurally related to the enolic acid class of 4-hydroxy-1,2-benzothiazine carboxamides. They are used clinically to treat both acute and chronic inflammation by inhibiting the activity of the two cyclooxygenase (COX) isoforms, COX-1 and COX-2. Oxicams are structurally distinct from all other NSAIDs, exhibiting a novel binding pose in the COX active site. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding while two coordinated water molecules mediate a polar interaction between the oxicam and COX. The rotation of Leu-531 in the complex opens a new pocket, which is not used for binding other NSAIDs to the enzyme. This structure provides the basis for understanding documented structure-activity relationships within the oxicam class. In addition, from the oxicam template, a series of potent microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors represents a new direction for drug development. Here, we review the major route of oxicam synthesis and structure-activity for COX inhibition, as well as recent advances in oxicam-mediated mPGES-1 inhibition.
authors.affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research; Department of Biochemistry; Vanderbilt Institute of Chemical Biology.
authors.forename: Shu
authors.initials: S
authors.lastname: Xu
authors.forename: Carol A
authors.initials: CA
authors.lastname: Rouzer
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D000077239:Meloxicam; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000071876:Prostaglandin-E Synthases; D013843:Thiazines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013843:Thiazines; D013844:Thiazoles; D010894:Piroxicam; C013580:isoxicam; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000077239:Meloxicam
keywords: NSAIDs; cyclooxygenases; mPGES-1; oxicams