ABSTRACT
The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC(50) values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Quinolines/chemistry , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Humans , Mice , Mice, Nude , Microsomes/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Xenograft Model Antitumor Assays , src-Family Kinases/metabolismABSTRACT
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.
Subject(s)
Aniline Compounds/therapeutic use , Brain Ischemia/drug therapy , Neuroprotective Agents/therapeutic use , Nitriles/therapeutic use , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinolines/therapeutic use , src-Family Kinases/antagonists & inhibitors , Aniline Compounds/administration & dosage , Aniline Compounds/chemistry , Aniline Compounds/pharmacokinetics , Animals , Blood Platelets/drug effects , Blood Platelets/enzymology , Brain/drug effects , Brain/enzymology , Brain/metabolism , Brain Ischemia/enzymology , Capillary Permeability , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Flow Cytometry , Humans , Injections, Intravenous , Male , Molecular Structure , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Neuropsychological Tests , Nitriles/administration & dosage , Nitriles/chemistry , Nitriles/pharmacokinetics , Piperazines/administration & dosage , Piperazines/chemistry , Piperazines/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Rats, Wistar , Time FactorsABSTRACT
The thieno[2,3-b]pyridine-5-carbonitrile with a 5-indolylamine at C-4 and a phenyl group at C-2 had a moderate activity against PKCtheta. Optimization of the groups at C-4 and C-2 led to analog 29, which has an IC(50) value of 7.5nM for the inhibition of PKCtheta.
Subject(s)
Antineoplastic Agents/pharmacology , Isoenzymes/antagonists & inhibitors , Nitriles/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Thiophenes/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor/drug effects , Cell Line, Tumor/pathology , Inhibitory Concentration 50 , Mice , Mice, Knockout , Models, Chemical , Nitriles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
Of a series of 7-ethynyl-3-quinolinecarbonitriles, the most potent Src inhibitory activity was observed with 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927). Variation of the solubilizing amine tail or removal of the methoxy group from either C-6 of the quinoline core or C-5 of the aniline headpiece led to reduced activity.
Subject(s)
Nitriles/pharmacology , Quinolines/pharmacology , src-Family Kinases/antagonists & inhibitors , Amines , Aniline Compounds , Humans , Inhibitory Concentration 50 , Nitriles/chemical synthesis , Quinolines/chemical synthesis , Solubility , Structure-Activity RelationshipABSTRACT
New 4-phenylamino-3-quinolinecarbonitriles with a 7-ethynyl group substituted by a pyridine, phenyl or thiophene ring containing basic water solubilizing groups were prepared and evaluated as Src kinase inhibitors. Of these new analogs, potent activity was observed with compounds having a (2,4-dichloro-5-methoxyphenyl)amino group at C-4, a methoxy or ethoxy group at C-6, and a pyridyl group bearing a dimethylamine or N-methylpiperazine on the ethynyl group at C-7.
Subject(s)
Quinolines/pharmacology , Water/chemistry , src-Family Kinases/antagonists & inhibitors , Quinolines/chemistry , SolubilityABSTRACT
7-[(2,4-Dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitriles with various heteroaryl groups at C-2 are inhibitors of Src kinase activity. Of these new analogs, compounds substituted at C-2 by a 3,5-furan or a 2,5-pyridine had the best activity in the Src enzyme and cell assays.
Subject(s)
Nitriles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Kinetics , Mice , Mice, Nude , Neoplasms, Experimental/drug therapy , Nitriles/pharmacology , Nitriles/therapeutic use , Pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
2-phenyl-7-phenylaminothieno[3,2-b]pyridine-6-carbonitriles were recently reported to be inhibitors of Src kinase activity. In this study we present structure-activity relationships for additional thieno[3,2-b]pyridine-6-carbonitriles, modifying the substituents on the C-2 phenyl and C-7 phenylamino groups. Derivatives with various aminomethyl and aminoethyl substituents on the para position of the C-2 phenyl group retained the activity of the initial analogues. However, direct attachment of an amino group led to decreased activity. A 2,4-dichloro-5-methoxyphenylamino group at C-7 provided superior inhibition of Src enzymatic activity. Replacement of the C-2 phenyl group with a 3,5-substituted thiophene led to improved Src inhibitory activity compared to the parent compound, but other thiophene isomers were less active. One of the analogues reported here exhibited in vivo activity comparable to that of SKI-606, a related 3-quinolinecarbonitrile currently in clinical trials.
Subject(s)
Antineoplastic Agents/chemical synthesis , Nitriles/chemical synthesis , Pyridines/chemical synthesis , Thiophenes/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/enzymology , Humans , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics , Mice , Mice, Nude , Nitriles/chemistry , Nitriles/pharmacology , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Rats , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology , Transfection , Xenograft Model Antitumor Assays , src-Family Kinases/geneticsABSTRACT
Several new ethynyl- and ethenyl-4-phenylamino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing an ethenyl or ethynyl substituent at C-6 showed decreased Src inhibitory activity. Incorporation of an ethenylpyridine N-oxide group at C-7 provided 20b, a 0.6 nM inhibitor of Src enzymatic activity with excellent cellular potency.
Subject(s)
Quinolines/chemistry , src-Family Kinases/antagonists & inhibitors , Animals , Inhibitory Concentration 50 , Mice , Mice, Nude , Models, Chemical , Molecular Structure , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Thiophenes/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Structure-Activity Relationship , Thiophenes/pharmacologyABSTRACT
A series of 7-ethynyl and 7-ethenyl-4-anilino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing a C-6 methoxy group and 2,4-dichloro-5-methoxyaniline at C-4 showed optimal inhibition of Src enzymatic and cellular activity. The ethenyl and ethynyl groups were incorporated at C-7 utilizing a Stille, Heck, or Sonogashira coupling reaction.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , src-Family Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Nitriles/chemistryABSTRACT
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.
Subject(s)
Nitriles/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinolines/chemical synthesis , src-Family Kinases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Cell Line, Tumor , Humans , Nitriles/chemistry , Nitriles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
Several 7-alkoxy-4-anilino-3-quinolinecarbonitriles were synthesized and evaluated for Src kinase inhibitory activity. Optimal inhibition of both Src enzymatic and cellular activity was seen with analogues having a 2,4-dichloro-5-methoxyaniline group at C-4. Compound 18, which has a 1-methylpiperidinemethoxy group at C-7, showed in vivo activity in a xenograft model.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , src-Family Kinases/antagonists & inhibitors , Animals , Cell Line , Cell Transplantation , Fibroblasts/enzymology , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Nude , Rats , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A short synthesis of the hydantoin-containing marine sponge metabolites axinohydantoins is described. A key feature of the synthesis is a putative biomimetic, intramolecular cyclization of alpha-functionalized imidazolone 5, which affords the tricyclic pyrroloazepinone framework comprising 6. In addition, the conversion of imidazolones to alpha,beta-unsaturated hydantoins is outlined and represents a new approach to these heterocyclic systems.