0 citations
Discovery of a Potent, Selective, and Orally Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)
Journal of Medicinal Chemistry2008Vol. 51(13), pp. 3688–3691
Citations Over TimeTop 11% of 2008 papers
Longbin Liu, Aaron Siegmund, Ning Xi, Paula Kaplan‐Lefko, Karen Rex, April Chen, Jasmine Lin, Jodi Moriguchi, Loren Berry, Liyue Huang, Yohannes Teffera, Yajing Yang, Yihong Zhang, Steven F. Bellon, Matthew Lee, Roman Shimanovich, Annette Bak, Celia Dominguez, Mark H. Norman, Jean-Christophe Harmange, Isabelle Dussault, Tae‐Seong Kim
Abstract
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.
Related Papers
- → Diastereoselective synthesis of mixanpril, an orally active dual inhibitor of neutral endopeptidase and angiotensin converting enzyme(1995)17 cited
- → Pharmacokinetics of Four Tyrosine Kinase Inhibitors in Adult and Paediatric Chronic Myeloid Leukaemia Patients(2023)3 cited
- → ASH Annual Meeting 2012—Chronic Myeloid Leukemia Update(2013)1 cited
- → Pharmacokinetics of Four Tyrosine Kinase Inhibitors in Adult and Paediatric Chronic Myeloid Leukaemia Patients(2023)1 cited
- → Analysis of onset mechanism for tyrosine kinase inhibitor imatinib induced-left ventricular diastolic dysfunction(2020)