Nitric Oxide (NO)- and Nitroxyl (HNO)-Generating Diazeniumdiolates (NONOates): Emerging Commercial Opportunities

Larry   K.   Keefer

Abstract

Diazeniumdiolate ions are convenient and, for a variety of applications, uniquely advantageous nitric oxide (NO) dosage forms. Ionic diazeniumdiolates generate bioactive NO in physiological fluids truly spontaneously (i. e., without metabolism or redox activation), with reliable half-lives ranging from 2 seconds to 20 hours depending on the ions structure. They are generally simple-to-prepare solids with excellent shelf life and high NO content - up to 40% by weight. Very importantly from the pharmaceutical point of view, the ionic diazeniumdiolates can be easily derivatized to prodrug forms that can be activated for NO release enzymatically, photolytically, or by slowed hydrolysis, allowing for rational design of strategies for targeting pharmacological delivery of NO to sites of need without unwanted collateral exposure of other NO-sensitive compartments. In addition to their world-wide sale for use in probing the chemical biology of NO, published proof-of-concept studies with diazeniumdiolates suggest several more lucrative applications. These include: converting existing drugs and biologicals to NO-releasing form to improve performance and/or extend patent life; diazeniumdiolating medical devices for improved biocompatibility; anticancer drug discovery; use as surgical aids and for wound repair; field generation of NO gas; and nonmedical uses such as extending the post-harvest life of cut flowers. Future work aimed at exploiting the full clinical potential of diazeniumdiolate technology will be pursued in this laboratory and strongly encouraged in others, with a concurrent fundamental research effort to broaden the knowledge base from which further opportunities can be inferred [e. g., exploiting the very recent finding that some diazeniumdiolates appear to offer a versatile platform from which nitroxyl (HNO)-generating prodrugs can be developed].

Keywords: diazeniumdiolate, no-based therapies, restenosis, thromboresistant, biofouling, micropatterning, angioplasty, anticoagulant