Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach—Part 2

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 1; pp. 471 - 474
• Main Authors: Labroli, Marc, Paruch, Kamil, Dwyer, Michael P., Alvarez, Carmen, Keertikar, Kartik, Poker, Cory, Rossman, Randall, Duca, Jose S., Fischmann, Thierry O., 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; CDK; Cell cycle; 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; Inhibitors; 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; structure-activity relationships; Pyrazolo[1,5-a]pyrimidine; Inhibitors; CDK; CHK1; Kinase; Cell cycle; Cyclohexane derivatives; Molecular structure; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Enzyme inhibitor; Selectivity; X ray diffraction; Cyclin-dependent kinase; Signal transduction; Pyrazolopyrimidine derivatives; Structure activity relation; Piperidine derivatives; Pyrazole derivatives; Bromine Organic compounds; Chemical synthesis; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.10.114

Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.