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

The inhibition of PKC-{zeta} 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-{zeta}). 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-NH{sub 2} derivative. The analog displays good selectivity over other PKC isoforms ({alpha}, {beta}II, {gamma}, {delta}, {epsilon}, {mu}, {theta}, {eta} and {ell}/{lambda}) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).