Progress toward clinical application of the nitric oxide-releasing diazeniumdiolates

Diazeniumdiolates, compounds of structure R(1)R(2)NN(O)=NOR(3), which have also been called NONOates, have proven useful for treating an increasing diversity of medical disorders in relevant animal models. Here, I review the chemical features that make them such excellent starting points for designing materials capable of targeting reliable and controllable fluxes of bioactive NO for in vitro and in vivo applications. This is followed by a consideration of recent proof-of-concept studies that underscore what I believe to be the substantial clinical promise of such materials. Examples covered include progress toward inhibiting restenosis after angioplasty, preparing thromboresistant medical devices, reversing vasospasm, and relieving pulmonary hypertension. Together with a very recent report describing the beneficial effects of diazeniumdiolate therapy in a patient with acute respiratory distress syndrome, the results of the animal experiments support the prediction that a broad selection of problems in clinical medicine can be solved by judiciously mining the enormous variety of possible R(1)R(2)NN(O)=NOR(3) structures.