Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors

Abstract A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity ( c  log  D  = 4.4). Azaindole 5 was designed as an indole surrogate with the goal of lowering log  D and resulted in equipotent PAK1 inhibition with a 2-fold improvement in cellular potency over 1 . Structure–activity relationship studies around 5 identified additional 4-azaindole analogs with superior PAK1 biochemical activity ( K i 1 . The improvement in physicochemical properties translated to a 20-fold decrease in unbound clearance in mouse PK studies for azaindole 5 relative to indole 1 .