#C12922
Inventor(s): John Toscano, Daryl Guthrie
Unmet Need
An estimated 17.9 million people died from cardiovascular diseases in 2019, representing 32% of all global deaths (see WHO). Nitroglycerin has been used as a vasodilator to treat heart conditions for over 130 years. It wasn't until 2003 that scientists realized the beneficial effect was due to it being converted by the body to nitric oxide (NO). Nitroxyl (HNO) chemistry, which was largely ignored over the course of the 20th century, has experienced a resurgence since HNO and NO are redox-related. Treatment with HNO could provide a route as a drug treatment for cardiovascular disease. Due to its inherent reactivity, however, HNO cannot be used directly, and therefore must be generated within the body through the use of prodrugs. Therefore, there is a strong need to develop HNO prodrug compounds where the time scale for release within the body can be controlled by the chemistry.
Technology Overview
Researchers at Johns Hopkins have developed a novel hydroxylaminobarbituric acid (HABA) derivative class of molecules that donate HNO under non-enzymatic, physiological conditions. Researchers described substituent groups on HABA derivatives which are optimized against competitive rearrangement mechanisms that produce negligible HNO. The new substituent groups extend the half-life of the HNO donor in in vitro experiments. These compounds provide a scaffold for further substituent changes to optimize for physiochemical and pharmacological properties. HNO has a short half-life in the body, so being able to control its release rate is desirable as a potential drug treatment.
Stage of Development
Experimental data available.
Publications
Daryl A. Guthrie, et al. Development of N-Substituted Hydroxylamines as Efficient Nitroxyl
(HNO) Donors. J. Am. Chem. Soc. 2012, 134, 1962-1965
Daryl A. Guthrie, et al. Curtailing the Hydroxylaminobarbituric Acid–Hydantoin Rearrangement To Favor HNO Generation. J. Org. Chem. 2015, 80, 3, 1349-1356
