1. Academic Validation
  2. 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 kinase inhibitor with preferential affinity for the activated state of c-Met

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 kinase inhibitor with preferential affinity for the activated state of c-Met

  • J Med Chem. 2013 Mar 28;56(6):2294-310. doi: 10.1021/jm301619u.
Alan B Northrup 1 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
Affiliations

Affiliation

  • 1 Department of Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, BMB-3, Boston, Massachusetts 02115, USA. alan_northrup@merck.com
Abstract

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.

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