Pyrazolone based TGFbetaR1 kinase inhibitors

  • Bioorg Med Chem Lett. 2010 Jan 1;20(1):326-9. doi: 10.1016/j.bmcl.2009.10.108.
Kevin Guckian  1 ,  Mary Beth Carter ,  Edward Yin-Shiang Lin ,  Michael Choi ,  Lihong Sun ,  P Ann Boriack-Sjodin ,  Claudio Chuaqui ,  Benjamin Lane ,  Kam Cheung ,  Leona Ling ,  Wen-Cherng Lee
Affiliations
PMID: 19914068 DOI: 10.1016/j.bmcl.2009.10.108
Abstract

Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.