Replacement of the carboxylic acid function of indomethacin with reversed hydroxamic acids converted this selective cyclooxygenase (CO) inhibitor into dual inhibitors of CO and 5-lipoxygenase (5-LO). Prostaglandins and leukotrienes are potent mediators of inflammation1,2 that are derived from arachidonic acid (AA) via the CO and 5-LO metabolic pathways respectively. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the CO pathway.3 The long-term use of NSAIDs often results in gastrointestinal ulcerations. Although the mechanism by which these side effects arise is not fully understood, decreased production of antisecretory and cytoprotective prostaglandins and increased production of pro-inflammatory leukotrienes have been implicated.4 Dual inhibitors of CO and 5-LO are predicted to exhibit a profile featuring improved efficacy and reduced gastrointestinal side effects.5 This paper describes the conversion of the NSAID indomethacin (1a) into dual inhibitors of CO and 5-LO by incorporating 5-LO inhibiting pharmacophores into its structure. Stimulated by Corey's initial account that the hydroxamic acid analog of AA is a potent selective 5-LO inhibitor, our laboratories converted various NSAIDs to their corresponding hydroxamic acids.7 This work revealed that via this transformation, indomethacin (1a) could be converted to a dual inhibitor. However, it was clearly demonstrated that hydroxamic acids of this structural type are readily and completely metabolized to the parent carboxylic acids.8 The reversal of the hydroxamic acid moiety in various selective 5-LO inhibitors was shown to greatly reduce the metabolic degradation while maintaining potent 5-LO inhibitory activity.9 Metabolic stability was further enhanced by the substitution of a methyl group on the carbon adjacent to the hydroxamic acid nitrogen.10 In light of these observations, it was our goal to prepare a variety of metabolically stable reversed hydroxamates of indomethacin (structure II) and determine their potencies as dual inhibitors.