Abstract
This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacokinetics
-
Aurora Kinases
-
Benzimidazoles / chemical synthesis
-
Benzimidazoles / chemistry*
-
Benzimidazoles / pharmacokinetics
-
Cell Line, Tumor
-
Humans
-
Mice
-
Protein Kinase Inhibitors / chemical synthesis
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / pharmacokinetics
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / metabolism
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Benzimidazoles
-
Protein Kinase Inhibitors
-
2-aminobenzimidazole
-
Aurora Kinases
-
Protein Serine-Threonine Kinases