Nitric Oxide Donors: A Continuing Opportunity in Drug Design

This chapter illustrates the advantageous, much unique, chemical, and pharmacological properties of nitric oxide (NO) donor compound class by showing how the accumulating knowledge are used in this area in attempting to design solutions to two clinical problems for which adequate pharmacological strategies do not currently exist. These are restenosis following angioplasty and other mechanical interventional procedures for vascular repair and the failure of small-caliber synthetic vascular grafts used to replace obstructed arteries. The chapter attempts to show how the versatility of compounds containing the N₂O₂⁻ functional group might be harnessed to solve important clinical problems. As such, agents releases NO at a first-order rate with a half-life of approximately one day in physiological buffer, these compounds can be conveniently used to inhibit vascular smooth muscle cell proliferation in culture completely for a prolonged period with no detectable toxic effect. As the half-life of NO release from such agents generally increases with pH, this is used to design an infusion device in which a homolog with a half-life of 1 min at pH 7.4 could be stabilized in a slightly alkaline reservoir and continuously neutralized 1 min before delivery as an NO-rich solution into the bloodstream to inhibit platelet deposition at an otherwise thrombogenic site. Finally, by incorporating the N₂O₂⁻ functional group into a polymeric matrix, an NO point source has been prepared that, when used as a coating for commercial vascular implants, greatly reduced thrombogenicity in a preliminary experiment.