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.
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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)
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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
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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)
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