Nitric oxide-releasing drugs - A novel class of effective and safe therapeutic agents

Nitric oxide (NO) deficiency has been implicated in many pathologic processes, thus providing a solid biological basis for the use of NO replacement therapy. Exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate sufficient NO for normal biological functions. This theory has opened up the possibility of designing new drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner. This objective has been achieved by grafting an organic nitrate structure onto existing drugs through chemical spacers, such as aliphatic, aromatic, or a heterocyclic chain. The approach has led to the synthesis of several new chemical entities whose pharmacologic profile challenges the parent drug, not only on the basis of new properties, but also with respect to a better safety profile. In this article, a specific class of NO donors is reviewed, the nitric oxide-releasing non-steroidal antiinflammatory drugs, NO-NSAIDs. Recently discovered compounds, whose action depends on the combined properties of both the known drug and NO release, are illustrated. Two examples are described in detail: (1) nitric oxide-releasing aspirin, which has demonstrable innovative properties for treatment of vascular disorders and cancer; (2) nitro-derivatives of flurbiprofen that have shown encouraging results in models of Alzheimer's disease.