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


Authors: Antczak, C.; Veach, D. R.; Ramirez, C. N.; Minchenko, M. A.; Shum, D.; Calder, P. A.; Frattini, M. G.; Clarkson, B.; Djaballah, H.
Article Title: Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: Toward selective Abl inhibitors
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. © 2009 Elsevier Ltd. All rights reserved.
Keywords: controlled study; unclassified drug; human cell; antineoplastic agents; pyridines; drug targeting; imatinib; stem cell factor receptor; vasculotropin receptor; enzyme inhibition; antineoplastic activity; cancer cell culture; drug potency; cell line, tumor; abl kinase; cml; inhibitor; pyridopyrimidines; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; 6 (2,6 dichlorophenyl) 8 methyl 2 (phenylamino)pyrido[2,3 d]pyrimidin 7 one; abelson kinase; dasatinib; platelet derived growth factor receptor; protein serine threonine kinase; protein tyrosine kinase; pyrimidinone derivative; recombinant enzyme; cell assay; chronic myeloid leukemia; drug design; drug selectivity; drug specificity; drug synthesis; structure activity relation; substitution reaction; oncogene proteins v-abl; pyridones; pyrimidines; pyrimidinones; structure-activity relationship
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 19
Issue: 24
ISSN: 0960-894X
Publisher: Pergamon-Elsevier Science Ltd  
Date Published: 2009-12-15
Start Page: 6872
End Page: 6876
Language: English
DOI: 10.1016/j.bmcl.2009.10.085
PUBMED: 19889540
PROVIDER: scopus
PMCID: PMC3629380
DOI/URL:
Notes: --- - "Export Date: 30 November 2010" - "CODEN: BMCLE" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Darren Veach
    60 Veach
  2. Christophe Antczak
    40 Antczak
  3. David Shum
    52 Shum
  4. Christina Nicole Ramirez
    10 Ramirez
  5. Paul A Calder
    9 Calder