title: ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia.
abstract: 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.
authors.affiliation: Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK. oneill_michael_j@lilly.com
authors.forename: M J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: T K
authors.initials: TK
authors.lastname: Murray
authors.forename: D R
authors.initials: DR
authors.lastname: McCarty
authors.forename: C A
authors.initials: CA
authors.lastname: Hicks
authors.forename: C P
authors.initials: CP
authors.lastname: Dell
authors.forename: K E
authors.initials: KE
authors.lastname: Patrick
authors.forename: M A
authors.initials: MA
authors.lastname: Ward
authors.forename: D J
authors.initials: DJ
authors.lastname: Osborne
authors.forename: T R
authors.initials: TR
authors.lastname: Wiernicki
authors.forename: C R
authors.initials: CR
authors.lastname: Roman
authors.forename: D
authors.initials: D
authors.lastname: Lodge
authors.forename: J H
authors.initials: JH
authors.lastname: Fleisch
authors.forename: J
authors.initials: J
authors.lastname: Singh
mesh_terms: D000578:Amidines / Q000493:pharmacokinetics*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005849:Gerbillinae; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors
chemical_list: C102136:ARL 17477; D000578:Amidines; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase