title: Development and characterization of glutamyl-protected N-hydroxyguanidines as reno-active nitric oxide donor drugs with therapeutic potential in acute renal failure.
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.
authors.affiliation: EASTChem, School of Chemistry and Centre for Biomolecular Sciences, The University of St. Andrews , North Haugh, St. Andrews KY16 9ST, U.K.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Philip
authors.initials: P
authors.lastname: Milliken
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kulczynska
authors.forename: Alex M Z
authors.initials: AM
authors.lastname: Slawin
authors.forename: Adele
authors.initials: A
authors.lastname: Gordon
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Botting
authors.forename: Ian L
authors.initials: IL
authors.lastname: Megson
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry; D006146:Guanidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006898:Hydroxylamines; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D006146:Guanidines; D006898:Hydroxylamines; D020030:Nitric Oxide Donors; D011355:Prodrugs; D014665:Vasodilator Agents; D009569:Nitric Oxide; D018698:Glutamic Acid; C029604:hydroxyguanidine