O2-sulfonylethyl protected isopropylamine diazen-1-ium-1,2-diolates as nitroxyl (HNO) donors: synthesis, β-elimination fragmentation, HNO release, positive inotropic properties, and blood pressure lowering studies.

Abstract

New types of nonexplosive O(2)-sulfonylethyl protected (-CH(2)CH(2)SO(2)R; R = OMe, NHOMe, NHOBn, Me) derivatives of isopropylamine diazen-1-ium-1,2-diolate (IPA/NO) (2-5) were developed that are designed to act as novel HNO donors. These compounds, with suitable half-lives (6.6-17.1 h) at pH 7.4, undergo a base-induced β-elimination reaction that releases a methyl vinyl sulfone product and the parent IPA/NO anion which subsequently preferentially releases HNO (46-61% range). Importantly, the O(2)-methylsulfonylethyl compound 5 exhibited a significant in vitro inotropic effect up to 283% of the baseline value and increased the rates of contraction and relaxation but did not induce a chronotropic effect. Furthermore, compound 5 (22.5 mg/kg po dose) provided a significant reduction in blood pressure up to 6 h after drug administration. All these data suggest that O(2)-sulfonylethyl protected derivatives of IPA/NO, which are efficient HNO donors, could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.

• Authors: Zhangjian Huang, Jatinder Kaur, Atul Bhardwaj, Nasser Alsaleh, Julie A Reisz, Jenna F DuMond, S Bruce King, John M Seubert, Yihua Zhang, Edward E Knaus
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 22 Pg. 10262-71 (Nov 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23072318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• Cardiotonic Agents
• Nitric Oxide Donors
• Nitrogen Oxides
• O2-(2-methylsulfonylethyl) 1-(isopropylamino)diazen-1-ium-1,2-diolate
• Sulfones
• Triazenes
• Nitric Oxide
• nitroxyl

Topics

• Animals
• Antihypertensive Agents (chemical synthesis, pharmacology)
• Blood Pressure (drug effects)
• Cardiotonic Agents (chemical synthesis, pharmacology)
• Chromatography, Liquid
• Half-Life
• Heart (drug effects)
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Structure
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (metabolism)
• Nitrogen Oxides (metabolism)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Structure-Activity Relationship
• Sulfones (chemical synthesis, pharmacology)
• Triazenes (chemical synthesis, pharmacology)