Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1

Michael P Dwyer; Kamil Paruch; Marc Labroli; Carmen Alvarez; Kerry M Keertikar; Cory Poker; Randall Rossman; Thierry O Fischmann; Jose S Duca; Vincent Madison; David Parry; Nicole Davis; Wolfgang Seghezzi; Derek Wiswell; Timothy J Guzi

doi:10.1016/j.bmcl.2010.10.113

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1

Bioorg Med Chem Lett. 2011 Jan 1;21(1):467-70. doi: 10.1016/j.bmcl.2010.10.113. Epub 2010 Oct 27.

Authors

Michael P Dwyer¹, Kamil Paruch, Marc Labroli, Carmen Alvarez, Kerry M Keertikar, Cory Poker, Randall Rossman, Thierry O Fischmann, Jose S Duca, Vincent Madison, David Parry, Nicole Davis, Wolfgang Seghezzi, Derek Wiswell, Timothy J Guzi

Affiliation

¹ Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. [email protected]

PMID: 21094608
DOI: 10.1016/j.bmcl.2010.10.113

Abstract

The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.

MeSH terms

Binding Sites
Catalytic Domain
Checkpoint Kinase 1
Crystallography, X-Ray
Cyclin-Dependent Kinase 2 / antagonists & inhibitors
Cyclin-Dependent Kinase 2 / metabolism
Drug Evaluation, Preclinical
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Kinases / chemistry*
Protein Kinases / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
pyrazolo(1,5-a)pyrimidine
Protein Kinases
Checkpoint Kinase 1
Cyclin-Dependent Kinase 2