Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors

Abstract

The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC₅₀ values in the range of 500 nm. In a comparative computational study, these data were analyzed and rationalized in light of docking studies.

Keywords: docking; drug design; focused library; kinase inhibition; nitrogen heterocycles; scaffolds.