2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: Design and synthesis of a potent and isoform selective PKC-ζ inhibitor

The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH2 derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).

The design and synthesis of a potent and isoform selective PKCw-ζ (9, IC50 = 5.2 nM, 10- to 20,000-fold selective over other PKC isoforms, 200-fold selective over CDK-2) inhibitor is reported.Figure optionsDownload as PowerPoint slide