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
  • 1. Department of Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, BMB-3, Boston, Massachusetts 02115, USA. [email protected]
PMID: 23379595 DOI: 10.1021/jm301619u
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.

Products