Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors
- 29 December 2008
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 52 (2), 278-292
- https://doi.org/10.1021/jm800790t
Abstract
The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRβ with IC50 values <0.1 μM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.Keywords
This publication has 28 references indexed in Scilit:
- Phase 2 Studies of Sunitinib and AG013736 in Patients with Cytokine-Refractory Renal Cell CarcinomaClinical Cancer Research, 2007
- Aromatic Interactions with Phenylalanine 691 and Cysteine 828: A Concept for FMS-like Tyrosine Kinase-3 Inhibition. Application to the Discovery of a New Class of Potential Antileukemia AgentsJournal of Medicinal Chemistry, 2006
- 4-(Aminoalkylamino)-3-benzimidazole-quinolinones as potent CHK-1 inhibitorsBioorganic & Medicinal Chemistry Letters, 2006
- Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitorMolecular Cancer Therapeutics, 2006
- Regioselective hydrolysis of aromatic dinitriles using a whole cell catalystJournal of the Chemical Society, Perkin Transactions 1, 1994
- Antifolate and antibacterial activities of 6-substituted 2,4-diaminoquinazolinesEuropean Journal of Medicinal Chemistry, 1992
- Exclusive Ortho Cyanation and Alkylthiocarbonylation of Anilines and Phenols Using Boron TrichlorideSynthetic Communications, 1990
- Benzimidazole condensed ring systems. 4. New approaches to the synthesis of substituted pyrimido[1,6‐a]‐benzimidazole‐1,3(2H,5H)‐dionesJournal of Heterocyclic Chemistry, 1989
- cine and tele Substitutions in the reaction of 2,3-dinitroaniline with secondary aminesJournal of the Chemical Society, Chemical Communications, 1980
- ISOLATION OF A TUMOR FACTOR RESPONSIBLE FOR ANGIOGENESISThe Journal of Experimental Medicine, 1971