Nitric oxide (NO) and nitroxyl (HNO) are implicated in cardiovascular, nervous and immune system responses. However, therapeutic applications have lagged due to the metastability of both NO and HNO which requires that either be generated in situ by HNO or NO donors. Diazeniumdiolates have proven to be valuable NO donors as they are stable as sodium salts but will release NO (or HNO) under physiological conditions. O2-alkylation or –arylation of these stable zwitterionic salts form stable pro-drugs which have found application in hypertension, cancer or as anti-microbials. The synthesis of diazeniumdiolates (DAZDs) was demonstrated in 1960 by Drago et al., however this method has proven challenging due to high N2O concentrations and flammable solvents which can lead to detonation. Merck Process Research developed a safer and scalable method, which has expanded the scope of DAZDs into sterically hindered dialkylamines and primary amines. Modification of the amine moiety on the diazeniumdiolate has enabled tuning of the NO release rate and enabled varying of the NO/HNO ratios for primary amine DAZDs. This presentation will describe the next generation synthesis of dialkylamine and primary amine diazeniumdiolates, the kinetics of decomposition and the NO/HNO pathways, and address the challenges of NO donors as therapeutic agents.

Discovery and development of novel diazeniumdiolate derivatives as nitric oxide donors

2019 Fall National Meeting

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