Aurora Kinase Inhibitors Based on the Imidazo[1,2-a]pyrazine Core: Fluorine and Deuterium Incorporation Improve Oral Absorption and Exposure

• Published in: Journal of medicinal chemistry Vol. 54; no. 1; pp. 201 - 210
• Main Authors: Kerekes, Angela D, Esposite, Sara J, Doll, Ronald J, Tagat, Jayaram R, Yu, Tao, Xiao, Yushi, Zhang, Yonglian, Prelusky, Dan B, Tevar, Seema, Gray, Kimberly, Terracina, Gaby A, Lee, Suining, Jones, Jennifer, Liu, Ming, Basso, Andrea D, Smith, Elizabeth B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13-01-2011
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Aurora Kinases; Biological Availability; Cell Line, Tumor; Deuterium; Dogs; Drug Screening Assays, Antitumor; Fluorine; Histones - metabolism; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Macaca fascicularis; Mice; Mice, Nude; Neoplasm Transplantation; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazines - chemical synthesis; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transplantation, Heterologous
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1010995

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.