In the present studies, we have evaluated the effects of N-[4-(2-¿[(3-Chlorophenyl)methyl]amino¿ethyl)phenyl]-2-thiophenecarbo ximidamide 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 IC(50) values for
ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 microM, 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.