On the way toward designing next-generation nonsteroidal anti-inflammatory drugs: amtolmetin guacil

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main component of symptomatic treatment of patients with rheumatic disorders. The use of these drugs reduces the intensity of the most unpleasant symptoms and improves patients’ quality of life. Unfortunately, NSAID therapy is limited by the risk of dangerous gastric and cardiovascular complications. Researchers all over the world are involved in designing new drugs belonging to this family that would be characterized by increased safety. These drugs include coxibs (selective cyclooxygenase-2 (COX-2) inhibitors), combination drugs containing NSAIDs and gastroprotector agents (misoprostol, H2 blockers, proton pump inhibitors), COX2/LOG2 (lipoxygenase 2) inhibitors, and COX-inhibiting nitric oxide donors (CINODs). However, all these drugs proved to have serious drawbacks. Some of them are being actively used; launching of other drugs has been stopped at the stage of clinical trials; while the others were abandoned because of inadequate efficacy/tolerability ratio. A new representative of improved NSAIDs, amtolmetin guacil (AMG), was synthesized from tolmetin, a nonselective NSAID. As opposed to tolmetin, AMG has a number of gastroprotective properties. The most important one is that it increases NO concentration in the mucous membrane of the gastrointestinal tract. The pharmacological features of AMG are discussed; the data obtained during pre-clinical and clinical trials are reported.