NEW YORK (Reuters Health) - Researchers at Johns Hopkins University have set out to “rationally design” a new class of nitroxyl precursors, called diazeniumdiolates, as an alternative to pure nitric oxide donors for the treatment of cardiac failure.
Dr. John P. Toscano presented his group’s findings to date at the American Chemical Society’s 228th annual meeting in Philadelphia.
His work follows that reported earlier using the older nitroxyl precursor, Angeli’s salt (see Reuters Health report, April 14, 2003). In that study investigators found that the nitroxyl anion produces both a positive and a negative inotropic response, while nitric oxide provides only a relaxation response.
The investigators believe that nitroxyl precursors will eventually be used to protect the cardiovascular system from further damage during heart failure and to restore function to organs already affected.
“Compared with nitric oxide, however, much less is known about the fundamental solution chemistry of this deceptively complicated system,” Dr. Toscano wrote in his meeting abstract.
“We are excited that this is a new class of drugs, an alternative to standard nitroxyl (HNO) donors people have been using since the 1800s,” Dr. Toscano told Reuters Health. “But for us to reach something that is practically useful, we really have to pay close attention to what the byproducts are.”
Currently, the byproducts of diazeniumdiolates “are not benign,” he added. “What we can do as chemists is modify the structure in such a way so that the byproduct is not going to be an issue.”
Another fundamental property of nitroxyl is it propensity to dimerize, that is, to react with itself to make stable, biologically innocuous products, Dr. Toscano continued.
“From a practical point of view, if you have a donor that releases nitroxyl very, very fast, you will be generating a high initial concentration of nitroxyl and probably losing a fair amount of it to the dimerization reaction before it can do anything biologically useful,” he explained.
“This is part of our interest in developing new donors that have varying half lives, so they can deliver nitroxyl at different rates. We hope that if we can slow the rate of delivery, we might get the same effect with a lower dosage.”
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