- Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity against VEGFR2, p38α, and B-Raf
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A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an in vivo tool compound 47 (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold). Compound 47 demonstrated positive cardioprotective outcomes in a mouse model of ischemia/reperfusion cardiac injury, indicating that optimized exemplars from this series, such as 47, are favorable leads for discovering novel medicines for cardiac diseases.
- Cheung, Mui,Desai, Tina A.,Fries, Harvey,Gatto, Gregory J.,Graves, Alan P.,Holt, Dennis A.,Kallander, Lara S.,Patterson, Jaclyn R.,Shewchuk, Lisa,Stoy, Patrick,Totoritis, Rachel,Wang, Liping
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p. 15651 - 15670
(2021/11/16)
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- MODULATORS OF MULTIPLE KINASES
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Compound structures are provided which should modulate various selected kinases thereby regulating the corresponding kinase signal pathways. These pathways have been shown to regulate biological functions. The compounds, and similar variants, will be useful in therapeutic or diagnostic methods related to said kinases. In particular, improved effects on functional pathways mediated by kinases can be achieved by modulating selected combinations of kinases.
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Page/Page column 87
(2008/06/13)
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- BENZIMIDAZOLYL DERIVATIVES
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The invention relates to the novel compounds of formula (I) wherein R1, R1 , L, E, G, M, Q, U, R2, m, p and q are defined as in claim 1. The novel compounds are tyrosinkinase inhibitors, especially TIE-2 inhibitors, and Ra
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Page/Page column 76-77
(2008/06/13)
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- BENZIMIDAZOLE CARBOXAMIDES AS RAF KINASE INHIBITORS
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The present invention relates to benzimidazole carboxamides of formula (I), the use of the compounds of formula (I) as inhibitors of as inhibitors of one or more kinases, the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient. Accordingly, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by one or more kinase phathways, preferably by the raf kinase pathway, especially cancers.
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Page/Page column 127
(2008/06/13)
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- SEMICARBAZIDE DERIVATIVES AS KINASE INHIBITORS
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The present invention relates to semicarbazide derivatives of formula I, the use of the compounds of formula I as inhibitors of one or more kinases, the use of the compounds of formula I for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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Page/Page column 197
(2008/06/13)
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- MALONAMIDE DERIVATIVES
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The present invention relates to malonamide derivatives of formula (I): A-D-B, the use of the compounds of formula (I) as inhibitors of raf-kinase, the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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- BISARYLUREA DERIVATIVES
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The present invention relates to bisarylurea derivatives of formula (I), the use of the compounds of formula (I) as inhibitors of raf-kinase, the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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Page/Page column 179
(2010/02/13)
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- OXAMIDE DERIVATIVES USEFUL AS RAF-KINASE INHIBITORS
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The present invention relates to oxamide derivatives of Formula (I), the use of the compounds of Formula (I) as inhibitors of raf-kinase, the use of the compounds of Formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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Page 165; 166
(2008/06/13)
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- GLYCINAMIDE DERIVATIVES AS RAF-KINASE INHIBITORS
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The present invention relates to glycinamide derivatives of formula (I), the use of the compounds of formula (I) as inhibitors of raf-kinase, the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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Page/Page column 152
(2008/06/13)
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