Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 18; pp. 5296 - 5300
• Main Authors: Abraham, Sunny, Hadd, Michael J., Tran, Lan, Vickers, Troy, Sindac, Janice, Milanov, Zdravko V., Holladay, Mark W., Bhagwat, Shripad S., Hua, Helen, Ford Pulido, Julia M., Cramer, Merryl D., Gitnick, Dana, James, Joyce, Dao, Alan, Belli, Barbara, Armstrong, Robert C., Treiber, Daniel K., Liu, Gang
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2011; Elsevier
• Subjects: Animal models; Antineoplastic agents; Aurora kinase; Aurora Kinases; Biological and medical sciences; Dose-Response Relationship, Drug; General aspects; Medical sciences; mice; Molecular Structure; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases; rats; Serine/threonine kinase; Specificity; Stereoisomerism; Structure-Activity Relationship; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Tumor xenograft model; Tumors; Xenografts; Specificity; Aurora kinase; Serine/threonine kinase; Tumor xenograft model; Antineoplastic agent; Solid tumor; Intraperitoneal administration; Intravenous administration; Rat; Angular nitrogen heterocycle; Non-specific serine/threonine protein kinase; Cytotoxicity; Signal transduction; Structure activity relation; Bicyclic compound; Pyrazole derivatives; Colon; Chemical synthesis; Tumor cell; Human; Aminoalcohol; Ether; Enzyme; Aminoamide; Transferases; Rodentia; Enzyme inhibitor; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; Carboxamide; Fluorine Organic compounds; Pharmacokinetics; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.027

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described.
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.