The synthesis and SAR of new 4-(N-alkyl-N-phenyl)amino-6,7-dimethoxyquinazolines and 4-(N-alkyl-N-phenyl)aminopyrazolo[3,4-d]pyrimidines, inhibitors of CSF-1R tyrosine kinase activity

Myers, Michael R.; Setzer, Natalie N.; Spada, Alfred P.; Persons, P. E.; Ly, Cuong Q.; Maguire, Martin P.; Zulli, Allison L.; Cheney, Daniel L.; Zilberstein, Asher; Johnson, Susan E.; Franks, Carol F.; Mitchell, Karen

doi:10.1016/s0960-894x(97)00035-8

Cited by 30 publications

(16 citation statements)

References 4 publications

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“…To determine the effect of RPR101511A on other kinases, published protocols for CSF-1-receptor 16 and EGF-receptor 17 were followed. Protein kinase C (PKC) and protein kinase A (PKA) assays were conducted using commercially available kits according to the manufacturer's instructions (Sigma).…”

Section: In Vitro Assaysmentioning

confidence: 99%

Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A

Bilder¹,

Wentz²,

Leadley³

et al. 1999

Circulation

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Section: In Vitro Assaysmentioning

confidence: 99%

Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A

Bilder¹,

Wentz²,

Leadley³

et al. 1999

Circulation

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“…This essentially planar conformation was similar to the lowest-energy conformation of 4-anilinoquinazoline as calculated by quantum mechanical optimization using the 6-31G* basis set and was consistent with an NMR analysis of 4-anilino-6,7-dimethoxyquinazoline. 35 The 6,7-dimethoxy substituents were near the opening to the active site with methyl groups close to the plane of the quinazoline ring system, in concert with conformations of o-dimethoxy groups observed in small molecule crystal structures. 36 A number of interactons between compound 2 and CDK2 appeared to control binding.…”

Section: Resultsmentioning

confidence: 83%

Termination of Color Charges

2000

J. Med. Chem.

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4-Anilinoquinazolines represent an important class of protein kinase inhibitor. Modes of binding for two members of this inhibitor class were determined by X-ray crystallographic analysis of one inhibitor (4-[3-hydroxyanilino]-6,7-dimethoxyquinazoline) in complex with cyclin-dependent kinase 2 (CDK2) and the other (4-[3-methylsulfanylanilino]-6,7-dimethoxyquinazoline) in complex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoquinazoline was bound in the ATP site with the quinazoline ring system oriented along the peptide strand that links the two domains of the protein and with the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoline accepted a hydrogen bond from a backbone NH (CDK2, Leu-83; p38, Met-109) of the domain connector strand, and aromatic hydrogen atoms at C2 and C8 interacted with backbone carbonyl oxygen atoms of the peptide strand. The anilino group of the CDK2-bound compound was essentially coplanar with the quinazoline ring system and occupied a pocket between Lys-33 and Phe-80. For the p38-bound inhibitor, the anilino group was angled out of plane and was positioned between Lys-53 and Thr-106 in a manner similar to that observed for the aryl substituent of the pyridinylimidazole class of inhibitor.

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“…4‐Anilino‐6,7‐dimethoxyquinazoline derivatives were reported as FMS kinase inhibitors . RPR‐108514A ( 23 , Fig.…”

Section: Classification Of Fms Kinase Inhibitorsmentioning

confidence: 99%

“…It was 67 times more selective for FMS than for EGF‐R. Pyrazolo[3,4‐ d ]pyrimidine bioisostere of 24 demonstrated the same potency against FMS but with higher selectivity over EGF‐R …”

Section: Classification Of Fms Kinase Inhibitorsmentioning

confidence: 99%

FMS Kinase Inhibitors: Current Status and Future Prospects

El‐Gamal

Anbar

Yoo

et al. 2012

Medicinal Research Reviews

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FMS, first discovered as the oncogene responsible for Feline McDonough Sarcoma, is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony-stimulating factor (M-CSF or CSF-1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. Overexpression of CSF-1 and/or FMS has been implicated in a number of disease states such as the growth of metastasis of certain types of cancer, in promoting osteoclast proliferation in bone osteolysis, and many inflammatory disorders. Inhibition of CSF-1 and/or FMS may help treat these pathological conditions. This article reviews FMS gene, FMS kinase, CSF-1, IL-34, and their roles in bone osteolysis, cancer biology, and inflammation. Monoclonal antibodies, FMS crystal structure, and small molecule FMS kinase inhibitors of different chemical scaffolds are also reviewed.

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The synthesis and SAR of new 4-(N-alkyl-N-phenyl)amino-6,7-dimethoxyquinazolines and 4-(N-alkyl-N-phenyl)aminopyrazolo[3,4-d]pyrimidines, inhibitors of CSF-1R tyrosine kinase activity

Cited by 30 publications

References 4 publications

Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A

Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A

Termination of Color Charges

FMS Kinase Inhibitors: Current Status and Future Prospects

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