The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of California

Johns Hopkins University

The University of Arizona

Louisiana State University and Agricultural & Mechanical College

Katrina M Miranda

David A Wink

David A Kass

Nazareno Paolocci

Jon M Fukuto

Debashree Basudhar

Larry K Keefer

Joseph E Saavedra

Martin Feelisch

Tatsuo Katori

Joseph Saavedra

Pasquale Pagliaro

Debra J Salmon

Daniela Andrei

The present disclosure provides methods utilizing the diazeniumdiolate-based prodrugs for the treatment of cancer via various mechanisms and procedures. The disclosure also provides kits comprising the diazeniumdiolate-based prodrugs.

Compositions and methods of diazeniumdiolate-based prodrugs for treating cancer

Disclosed is a compound of the formula (I) or a pharmaceutically acceptable salt thereof: (I) in which R, R, R, and Rare defined herein and pharmaceutical compositions thereof. Further provided is a method of treating various disorders, such as a disorder selected from the group consisting of a cardiovascular disorder, cancer, chronic pain, alcohol dependence, and inflammation in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt of formula (I). 

Nitroxyl (HNO) releasing compounds and uses thereof in treating diseases

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Method of treating ischemia/reperfusion injury with nitroxyl donors

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO(Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Nitroxyl progenitors in the treatment of heart failure

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO (Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy

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Tucson, AZ, United States of America

Katrina M Miranda