Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors.

Abstract

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.

• Authors: Michael Lainchbury, Thomas P Matthews, Tatiana McHardy, Kathy J Boxall, Michael I Walton, Paul D Eve, Angela Hayes, Melanie R Valenti, Alexis K de Haven Brandon, Gary Box, G Wynne Aherne, John C Reader, Florence I Raynaud, Suzanne A Eccles, Michelle D Garrett, Ian Collins
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 22 Pg. 10229-40 (Nov 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23082860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile
• Aminopyridines
• Antineoplastic Agents
• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• Protein Kinase Inhibitors
• Pyrimidines
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse

Topics

• Administration, Oral
• Aminopyridines (chemical synthesis, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacology)
• Checkpoint Kinase 1
• Child
• Colonic Neoplasms (drug therapy, enzymology)
• DNA Damage (drug effects)
• Drug Design
• Humans
• Mice
• Mice, Nude
• Mice, Transgenic
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (drug therapy, enzymology)
• Nuclear Proteins (genetics)
• Oncogene Proteins (genetics)
• Protein Kinase Inhibitors (administration & dosage, chemical synthesis, pharmacology)
• Protein Kinases (chemistry, metabolism)
• Pyrimidines (chemical synthesis, pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays