- PYRAZOLOPYRIDINE PYRAZOLOPYRIMIDINE AND RELATED COMPOUNDS
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In one aspect this invention relates generally to compounds of Formula: and sub-formulas thereof, or a tautomer of each thereof, a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, where X1, L1, L3, and R3 are described herein.
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- Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5- methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor
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In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N′-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.
- Dai, Yujia,Hartandi, Kresna,Ji, Zhiqin,Ahmed, Asma A.,Albert, Daniel H.,Bauch, Joy L.,Bouska, Jennifer J.,Bousquet, Peter F.,Cunha, George A.,Glaser, Keith B.,Harris, Christopher M.,Hickman, Dean,Guo, Jun,Li, Junling,Marcotte, Patrick A.,Marsh, Kennan C.,Moskey, Maria D.,Martin, Ruth L.,Olson, Amanda M.,Osterling, Donald J.,Pease, Lori J.,Soni, Niru B.,Stewart, Kent D.,Stoll, Vincent S.,Tapang, Paul,Reuter, David R.,Davidsen, Steven K.,Michaelides, Michael R.
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p. 1584 - 1597
(2008/02/01)
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- Indazole and benzisoxazole kinase inhibitors
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Compounds having the formula are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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