ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Fluorine , Imidazoles/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Aurora Kinases , Biological Availability , Cell Line, Tumor , Deuterium , Dogs , Drug Screening Assays, Antitumor , Histones/metabolism , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Macaca fascicularis , Mice , Mice, Nude , Neoplasm Transplantation , Phosphorylation , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.