Discovery of indazoles as inhibitors of Tpl2 kinase

Yonghan Hu; Derek Cole; Rajiah Aldrin Denny; David R Anderson; Manus Ipek; Yike Ni; Xiaolun Wang; Suvit Thaisrivongs; Timothy Chamberlain; J Perry Hall; Julie Liu; Michael Luong; Lih-Ling Lin; Jean-Baptiste Telliez; Ariamala Gopalsamy

doi:10.1016/j.bmcl.2011.06.065

Discovery of indazoles as inhibitors of Tpl2 kinase

Bioorg Med Chem Lett. 2011 Aug 15;21(16):4758-61. doi: 10.1016/j.bmcl.2011.06.065. Epub 2011 Jun 22.

Authors

Yonghan Hu¹, Derek Cole, Rajiah Aldrin Denny, David R Anderson, Manus Ipek, Yike Ni, Xiaolun Wang, Suvit Thaisrivongs, Timothy Chamberlain, J Perry Hall, Julie Liu, Michael Luong, Lih-Ling Lin, Jean-Baptiste Telliez, Ariamala Gopalsamy

Affiliation

¹ Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA.

PMID: 21742493
DOI: 10.1016/j.bmcl.2011.06.065

Abstract

Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Models, Molecular
Molecular Structure
Monocytes / enzymology
Monocytes / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Indazoles
Proto-Oncogene Proteins
MAP Kinase Kinase Kinases
MAP3K8 protein, human