Oxicams, a class of nonsteroidal anti‐inflammatory drugs and beyond

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. © 2014 IUBMB Life, 66(12):803–811, 2014