Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors

  • Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6. doi: 10.1016/j.bmcl.2009.10.085.
Christophe Antczak  1 ,  Darren R Veach ,  Christina N Ramirez ,  Maria A Minchenko ,  David Shum ,  Paul A Calder ,  Mark G Frattini ,  Bayard Clarkson ,  Hakim Djaballah
Affiliations
  • 1. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10065, USA. [email protected]
PMID: 19889540 DOI: 10.1016/j.bmcl.2009.10.085
Abstract

We report the design, synthesis, and structure-activity relationship (SAR) of a series of novel pyrido[2,3-d]pyrimidin-7-one compounds as potent Abl kinase inhibitors. We evaluate their specificity profile against a panel of human recombinant kinases, as well as their biological profile toward a panel of well-characterized Cancer cell lines. Our study reveals that substitutions in the 3- and 4-positions of the phenylamino moiety lead to improved potency and improved selectivity both in target-based and cell-based assays. Altogether, our results provide an insight into the SAR of pyrido[2,3-d]pyrimidin-7-ones for the development of drug candidates with improved potency and selectivity for the targeted treatment of CML.