Document Report Card

ID: ALA2396521

Journal: J Med Chem

Title: Development and characterization of glutamyl-protected N-hydroxyguanidines as reno-active nitric oxide donor drugs with therapeutic potential in acute renal failure.

Authors: Zhang Q, Milliken P, Kulczynska A, Slawin AM, Gordon A, Kirkby NS, Webb DJ, Botting NP, Megson IL.

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 γ-glutamyl transpeptidase (γ-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 γ-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 μM). The data confirm that glutamate protection of N-hydroxyguanidines is an approach that might hold promise in ARF.

CiteXplore: 23782349

DOI: 10.1021/jm400146r