Synthesis and Biological Evaluation of Ω-(N,N,N-Trialkylammonium)alkyl Esters and Thioesters of Carboxylic Acid Nonsteroidal Antiinflammatory Agents

A series of novel ω-(N,N,N-trialkylammonium)alkyl ester and thioester derivatives [RCOM(CH2) n NR3+X−, M = O or S, n = 2–6, X = I or Cl] of 11 nonsteroidal antiinflammatory carboxylic acid agents (naproxen, ketorolac, indomethacin, ibuprofen, sulindac, ketoprofen, flufenamic acid, mefenamic acid, zomepirac, etodolac, and tifurac) was prepared and evaluated for their antiinflammatory, analgesic, and gastrointestinal erosive properties. In general, each prodrug retained the antiinflammatory activity characteristic of the corresponding parent drug but exhibited moderately to greatly reduced gastrointestinal erosive properties and significantly reduced analgetic potencies. This profile is likely due to a combination of factors including the rate of hydrolysis of the esters in the stomach, gut, and plasma, changes in the locus of absorption of the prodrug or nonsteroidal antiinflammatory drug (NSAID), and altered metabolic disposition patterns resulting from these changes. The results obtained from the compounds of this series indicate that esters of this general class may offer a means to modulate both the aqueous/lipid solubility and the hydrolytic/enzymatic cleavage indices of NSAID prodrugs which potentially possess a more favorable therapeutic ratio of antiinflammatory to gastrointestinal erosive activities.