Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: Optimization of BX-517

Based on the lead compound BX-517, a series of C-4′ substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4′ of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.

Optimization of BX-517 afforded 7b, an inhibitor of PDK1 with improved physicochemical properties.Figure optionsDownload as PowerPoint slide