We previously reported that several 7-alkoxy-4-phenylamino-3-quinolinecarbonitriles were potent inhibitors of Src kinase activity. We disclose here a new highly efficient and versatile route to these compounds, which are also potent inhibitors of Abl kinase.
We disclose here a new class of kinase inhibitors, obtained by replacing the phenyl ring of a 3-quinolinecarbonitrile system with a thiophene ring. When suitably substituted, the resultant 7-phenylaminothieno[3,2-b]pyridine-6-carbonitrile analogues show potent inhibition of Src kinase activity.
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 longterm 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.Ischemic stroke is a life-threatening disorder, with no effective therapy except for intravascular thrombolysis with recombinant tissue plasminogen activator or, in some instances, surgical removal of the obstructing blood clot with interventional devices (Donnan et al., 2008;Zaleska et al., 2009). However, the risk of hemorrhage and a restrictive 3-to 4.5-h treatment window (Hacke et al., 2008) reduce the pool of patients eligible for treatment with recombinant tissue plasminogen activator to only 5 to 8%. Despite continued improvement in our understanding of mechanisms underlying ischemic damage and the identification of numerous neuroprotective agents effective in animal models, no agent has yet demonstrated significant benefit in the clinic (O'Collins et al., 2006;Savitz and Fisher, 2007;Zaleska et al., 2009). Hence, the development of stroke therapeutic agents remains a daunting challenge as does the urgent need for new agents.The Src family of nonreceptor protein tyrosine kinases (PTKs) coordinate a broad spectrum of physiological responses including extracellular signals derived from growth facto...
An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1H-imidazoles (6) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters that affect the key intramolecular cyclization to build the imidazole ring. Additional information on the reaction mechanism of this step was obtained by carrying out a flow NMR experiment. In order to complete the proof of concept, the iodo-imidazole intermediate was converted to two ethynyl imidazoles (6a, b) using metal-catalyzed reactions.
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