#C14009
Inventor(s): John Toscano, Saghar Nourian, 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 O-substituted hydroxamic acid derivatives with carbon-based leaving groups that release HNO via hydrolysis of nitrosocarbonyl intermediate under physiologically relevant conditions non-enzymatically. Nitrosocarbonyls are transient electrophiles that react with water to generate HNO. The amount of HNO released is mainly dependent on the nature of the leaving group and reactivity of the nitrosocarbonyl intermediate and can be tuned accordingly. 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 is available.
Publication
Nourian, S., et al. Nitrosocarbonyl release from O-substituted hydroxamic acids with pyrazolone leaving groups. Tetrahedron. 2016, 72, 40, 6037-6042
