Oxindole derivatives as inhibitors of TAK1 kinase

Jeffrey W Lockman; Matthew D Reeder; Rosann Robinson; Patricia A Ormonde; Daniel M Cimbora; Brandi L Williams; J Adam Willardsen

doi:10.1016/j.bmcl.2011.01.077

Oxindole derivatives as inhibitors of TAK1 kinase

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1724-7. doi: 10.1016/j.bmcl.2011.01.077. Epub 2011 Jan 26.

Authors

Jeffrey W Lockman¹, Matthew D Reeder, Rosann Robinson, Patricia A Ormonde, Daniel M Cimbora, Brandi L Williams, J Adam Willardsen

Affiliation

¹ Departments of Chemistry, Myrexis, Inc., Salt Lake City, UT 84108, USA. [email protected]

PMID: 21316225
DOI: 10.1016/j.bmcl.2011.01.077

Abstract

Several series of oxindole analogues were synthesized and screened for inhibitory activity against transforming growth factor-β-activating kinase 1 (TAK1). Modifications around several regions of the lead molecules were made, with a distal hydroxyl group in the D region being critical for activity. The most potent compound 10 shows an IC(50) of 8.9 nM against TAK1 in a biochemical enzyme assay, with compounds 3 and 6 showing low micromolar cellular inhibition.

MeSH terms

Indoles / pharmacology*
Inhibitory Concentration 50
MAP Kinase Kinase Kinases / antagonists & inhibitors*
Oxindoles
Protein Kinase Inhibitors / pharmacology*

Substances

Indoles
Oxindoles
Protein Kinase Inhibitors
2-oxindole
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7