Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors

Sunny Abraham; Michael J Hadd; Lan Tran; Troy Vickers; Janice Sindac; Zdravko V Milanov; Mark W Holladay; Shripad S Bhagwat; Helen Hua; Julia M Ford Pulido; Merryl D Cramer; Dana Gitnick; Joyce James; Alan Dao; Barbara Belli; Robert C Armstrong; Daniel K Treiber; Gang Liu

doi:10.1016/j.bmcl.2011.07.027

Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5296-300. doi: 10.1016/j.bmcl.2011.07.027. Epub 2011 Jul 14.

Authors

Sunny Abraham¹, Michael J Hadd, Lan Tran, Troy Vickers, Janice Sindac, Zdravko V Milanov, Mark W Holladay, Shripad S Bhagwat, Helen Hua, Julia M Ford Pulido, Merryl D Cramer, Dana Gitnick, Joyce James, Alan Dao, Barbara Belli, Robert C Armstrong, Daniel K Treiber, Gang Liu

Affiliation

¹ Department of Medicinal Chemistry, Ambit Biosciences Corporation, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, United States.

PMID: 21802948
DOI: 10.1016/j.bmcl.2011.07.027

Abstract

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.

MeSH terms

Aurora Kinases
Dose-Response Relationship, Drug
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases
Stereoisomerism
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Protein Kinase Inhibitors
Triazines
Aurora Kinases
Protein Serine-Threonine Kinases