ARL 17477 dihydrochloride

ARL 17477 dihydrochloride is a selective and potent neuronal nitrogen oxide synthase (nNOS) inhibitor with IC50 values of 1 and 17μM for nNOS and endothelial NOS, respectively [1].
Neuronal NOS (nNOS) plays an important role in the development of ischaemic brain necrosis while endothelial NOS (eNOS) protects brain tissue through increasing ischaemic regional cerebral blood flow [1].
In rats after transient MCA occlusion, ARL 17477 (1mg/kg, 3mg/kg and 10mg/kg) reduced ischemic infarct volume by 53%, 23% and 6.5% respectively in a dose-dependent way. ARL 17477 (10 mg/kg) significantly reduced regional cerebral blood flow (rCBF) by 27±5.3% and 24±14.08%. Also, it reduced cortical NOS activity by 86±14.9% and 91±8.9% at 10 min or 3 h, respectively [2]. In the global cerebral ischaemia gerbil model, the combination of MK-801 with ARL 17477 provided 44% greater protection than the total protection or either alone. Likewise, the combination of LY293558 with ARL 17477 provided 35% greater protection than total protection of either compound alone [3].
References:
[1]. O'Neill MJ, Murray TK, McCarty DR, et al. ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. Brain Res, 2000, 871(2): 234-244.
[2]. Zhang ZG, Reif D, Macdonald J, et al. ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab, 1996, 16(4): 599-604.
[3]. Hicks CA, Ward MA, Swettenham JB, et al. Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia. Eur J Pharmacol, 1999, 381(2-3): 113-119.

ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia.[Pubmed:10899290]

Brain Res. 2000 Jul 21;871(2):234-44.

In the present studies, we have evaluated the effects of N-[4-(2- inverted question mark[(3-Chlorophenyl)methyl]amino inverted question markethyl)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.

Synergistic neuroprotective effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischaemia.[Pubmed:10554878]

Eur J Pharmacol. 1999 Sep 24;381(2-3):113-9.

We have investigated the neuroprotective effects of combining an NMDA or AMPA receptor antagonist with a nitric oxide synthase (NOS) inhibitor in the gerbil model of global cerebral ischaemia. Ischaemia was induced by occlusion of the common carotid arteries for 5 min. (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 0-imine (MK-801, 2.5 mg/kg i.p.) or (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)]decahydroisoq uinoline-3-carboxylic acid (LY293558, 20 mg/kg i.p.) and 7-nitroindazole (25 mg/kg i.p.) or N-[4-(2-[[(3-chlorophenyl)methyl]amino]ethyl) phenyl]-2-thiophenecarboximidamide dihydrochloride (ARL17477, 25 mg/kg i.p.) were administered alone or in combination (i.e., MK-801 with 7-nitroindazole or ARL17477 or LY293558 with 7-nitroindazole or ARL17477). In the present studies, both MK-801 and LY293558 provided significant degree of neuroprotection, while 7-nitroindazole and ARL17477 also provided some neuroprotection, which failed to reach significance in every case. However, the combination of MK-801 with 7-nitroindazole or ARL17477 provided 21% or 44% greater protection than the total protection or either alone. Likewise, the combination of LY293558 with 7-nitroindazole or ARL17477 provided 14.5% and 35% greater protection than total protection of either compound alone. These results indicate that several pathways contribute to ischaemic cell death and combining excitatory amino antagonists and NOS inhibitors provides greater protection than either alone. Therefore, combination therapy should be considered as an approach for treating ischaemic conditions.