Discovery of 1-[3-(1-Methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron Dual

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• 作者：Alan B. Northrup ; Matthew H. Katcher ; Michael D. Altman ; Melissa Chenard ; Matthew H. Daniels ; Sujal V. Deshmukh ; Danielle Falcone ; David J. Guerin ; Harold Hatch ; Chaomin Li ; Wei Lu ; Bart Lutterbach ; Timothy J. Allison ; Sangita B. Patel ; John F. Reilly ; Michael Reutershan ; Keith W. Rickert ; Craig Rosenstein ; Stephen M. Soisson ; Alexander A. Szewczak ; Deborah Walker ; Kevin Wilson ; Jonathan R. Young ; Bo-Sheng Pan ; Christopher J. Dinsmore
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2294-2310
• 全文大小：728K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.