Development and Characterization of Glutamyl-Protected N-Hydroxyguanidines as Reno-Active Nitric Oxide Donor Drugs with Therapeutic Potential in Acute Renal Failure

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• 作者：Qingzhi Zhang ; Philip Milliken ; Agnieszka Kulczynska ; Alex M. Z. Slawin ; Adele Gordon ; Nicholas S. Kirkby ; David J. Webb ; Nigel P. Botting ; Ian L. Megson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5321-5334
• 全文大小：617K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

Acute renal failure (ARF) has high mortality and no effective treatment. Nitric oxide (NO) delivery represents a credible means of preventing the damaging effects of vasoconstriction, central to ARF, but design of drugs with the necessary renoselectivity is challenging. Here, we developed N-hydroxyguanidine NO donor drugs that were protected against spontaneous NO release by linkage to glutamyl adducts that could be cleaved by 纬-glutamyl transpeptidase (纬-GT), found predominantly in renal tissue. Parent NO donor drug activity was optimized in advance of glutamyl adduct prodrug design. A lead compound that was a suitable substrate for 纬-GT-mediated deprotection was identified. Metabolism of this prodrug to the active parent compound was confirmed in rat kidney homogenates, and the prodrug was shown to be an active vasodilator in rat isolated perfused kidneys (EC₅₀ 50 渭M). The data confirm that glutamate protection of N-hydroxyguanidines is an approach that might hold promise in ARF.