Lead optimization on conventional non-steroidal anti-inflammatory drugs: an approach to reduce gastrointestinal toxicity.

Non-steroidal anti-inflammatory drugs are among the most widely used therapeutics, primarily for the treatment for pain and inflammation. Prostaglandins mediate a number of characteristic features of the body's response to tissue injury or inflammation. These outstanding effects include their cytoprotective properties in the gastrointestinal tract and control of renal functions in the kidney. Non-steroidal anti-inflammatory drugs exert their anti-inflammatory and antipyretic effects by blocking the production of prostanoids from arachidonic acid through inhibition ofcyclooxygenase enzyme. Classic non-steroidal anti-inflammatory drugs such as meclofenamic acid and indomethacin inhibit both isoforms of cyclooxygenase non-selectively or with low selectivity, exerting their anti-inflammatory activity via inhibiting cyclooxygenase-2, and their deleterious side-effects by inhibiting cyclooxygenase-1. To provide an effective treatment for inflammatory disorders, the design of novel non-steroidal anti-inflammatory drugs is aimed at obtaining new drugs, devoid of the side-effects commonly associated with conventional non-steroidal anti-inflammatory drugs. Several approaches have been explored to counteract the gastric damaging effects of these drugs. The chemical modification of non-steroidal anti-inflammatory drugs is aimed at improving their safety profile, where several studies have described the derivatization of the carboxylate function of non-steroidal anti-inflammatory drugs with less acidic analogs, which resulted in an increased anti-inflammatory activity with reduced ulcerogenicity. The present review explores the possible ways aimed to reduce ulcerogenicity.