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

Qingzhi Zhang, Philip Milliken, Agnieszka Kulczynska, Alex M. Z. Slawin, Adele Gordon, Nicholas S. Kirkby, David J. Webb, Nigel P. Botting, Ian L. Megson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 gamma-glutamyl transpeptidase (gamma-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 gamma-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 similar to 50 mu M). The data confirm that glutamate protection of N-hydroxyguanidines is an approach that might hold promise in ARF.

Original languageEnglish
Pages (from-to)5321-5334
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number13
DOIs
Publication statusPublished - 11 Jul 2013

Keywords

  • HYDROXY-L-ARGININE
  • RANDOMIZED CONTROLLED TRIAL
  • PROSTATE-SPECIFIC ANTIGEN
  • RAT-KIDNEY
  • TRANSFERASE TRANSPEPTIDASE
  • OMEGA-HYDROXYARGININE
  • RELAXING FACTOR
  • L-DOPA
  • SYNTHASE
  • PRODRUGS

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