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

In the present studies, we have evaluated the effects of N-[4-(2-{[( 3-Chlo rophenyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide dihydrochlor ide (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NO S (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound cros sed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischae mia in the rat. The IC50 values for ARL 17477 on human recombinant human nN OS and eNOS were 1 and 17 mu M, respectively. ARL 17477 (50 mg/kg i.p.) pro duced a significant reduction in the ischaemia-induced hippocampal damage f ollowing global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlus ion. In the endothelin-l 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 measu red at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17 477 protects against global ischaemia in gerbils and provides some reductio n in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaem ic conditions. (C) 2000 Elsevier Science B.V. All rights reserved.