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.
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.
Faculty of Pharmacy and Pharmaceutical Sciences,  University of Alberta , Edmonton, Alberta T6G 2E1, Canada.
Zhangjian
Z
Huang
Jatinder
J
Kaur
Atul
A
Bhardwaj
Nasser
N
Alsaleh
Julie A
JA
Reisz
Jenna F
JF
DuMond
S Bruce
SB
King
John M
JM
Seubert
Yihua
Y
Zhang
Edward E
EE
Knaus
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002853:Chromatography, Liquid; D006207:Half-Life; D006321:Heart / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*; D014226:Triazenes / Q000138:chemical synthesis / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; C577961:O2-(2-methylsulfonylethyl) 1-(isopropylamino)diazen-1-ium-1,2-diolate; D013450:Sulfones; D014226:Triazenes; D009569:Nitric Oxide; C039900:nitroxyl