title: Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemia.
abstract: Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma. Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short- and long-term neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3-30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4- to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Liang
authors.forename: Kevin
authors.initials: K
authors.lastname: Pong
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Huai-Ping
authors.initials: HP
authors.lastname: Ling
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mark
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Barrios Sosa
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Philip
authors.initials: P
authors.lastname: Frost
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D009570:Nitriles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C545736:4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(4-(4-methypiperazin-1-yl)but-1-ynyl)-3-quinolinecarbonitrile; D000814:Aniline Compounds; D018696:Neuroprotective Agents; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D019061:src-Family Kinases