Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis

Abstract

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as <b>12</b> with improved potency and selectivity. Additionally <b>12</b> demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective <b>21</b>, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.