A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: Synthesis, nitric oxide and nitroxyl release, in vitro hemodynamic, and anti-hypertensive studies

作者：Bhardwaj, Atul; Huang, Zhangjian; Kaur, Jatinder; Yang, Fenghua; Seubert, John M.; Knaus, Edward E.^*

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(9): 2769-2774.

DOI：10.1016/j.bmcl.2013.02.040

• Diazen-1-ium-1,2-diolate
• Nitroxyl and nitric oxide donors
• Positive inotrope
• Anti-hypertensive activity

1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8 min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2 h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7 mg kg(-1), po dose) provided a significant reduction in the blood pressure of mice up to 3 h post-drug administration. All these data suggest that compound 16 constitutes an attractive 'lead-compound' that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure.

• 出版日期2013-5-1
• 单位中国药科大学