ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia

Michael J. O'Neill, Tracey K. Murray, Deborah R. McCarty, Caroline A. Hicks, Colin P. Dell, Kelly E. Patrick, Mark A. Ward, David J. Osborne, Todd R. Wiernicki, Carlos R. Roman, David Lodge, Jerome H. Fleisch, Jai Pal Singh

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50 Scopus citations


In the present studies, we have evaluated the effects of N-[4-(2-{[(3-Chlorophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC50 values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 μM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)234-244
Number of pages11
JournalBrain research
Issue number2
StatePublished - Jul 21 2000



  • ARL 17477
  • Cerebral ischemia
  • Mongolian gerbil
  • Neuroprotection
  • Nitric oxide
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

O'Neill, M. J., Murray, T. K., McCarty, D. R., Hicks, C. A., Dell, C. P., Patrick, K. E., Ward, M. A., Osborne, D. J., Wiernicki, T. R., Roman, C. R., Lodge, D., Fleisch, J. H., & Singh, J. P. (2000). ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. Brain research, 871(2), 234-244.