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

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 467 - 470
• Main Authors: Dwyer, Michael P., Paruch, Kamil, Labroli, Marc, Alvarez, Carmen, Keertikar, Kerry M., Poker, Cory, Rossman, Randall, Fischmann, Thierry O., Duca, Jose S., Madison, Vincent, Parry, David, Davis, Nicole, Seghezzi, Wolfgang, Wiswell, Derek, Guzi, Timothy J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-01-2011; Elsevier
• Subjects: Antineoplastic agents; Binding Sites; Biological and medical sciences; Catalytic Domain; Checkpoint Kinase 1; CHK1; Crystallography, X-Ray; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - metabolism; Drug Evaluation, Preclinical; enzyme inhibitors; General aspects; Kinase; Medical sciences; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; protein kinases; Protein Kinases - chemistry; Protein Kinases - metabolism; pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolo[1,5-a]pyrimidine; pyrimidines; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Template; Pyrazolo[1,5-a]pyrimidine; CHK1; Kinase; Template; Molecular structure; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Enzyme inhibitor; Selectivity; X ray diffraction; Signal transduction; Pyrazolopyrimidine derivatives; Structure activity relation; Piperidine derivatives; Pyrazole derivatives; Chemical synthesis; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.113

The synthesis and SAR development of a pyrazolo[1,5-a]pyrimidine-based structural series is described which led to the identification of potent, selective CHK1 inhibitors such as 17r.
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.