Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases

  • Bioorg Med Chem Lett. 2012 Jul 15;22(14):4750-5. doi: 10.1016/j.bmcl.2012.05.067.
Michael L Curtin  1 ,  H Robin Heyman ,  Robin R Frey ,  Patrick A Marcotte ,  Keith B Glaser ,  James R Jankowski ,  Terrance J Magoc ,  Daniel H Albert ,  Amanda M Olson ,  David R Reuter ,  Jennifer J Bouska ,  Debra A Montgomery ,  Joann P Palma ,  Cherrie K Donawho ,  Kent D Stewart ,  Chris Tse ,  Michael R Michaelides
Affiliations
  • 1. Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. [email protected]
PMID: 22695126 DOI: 10.1016/j.bmcl.2012.05.067
Abstract

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly IP dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.