Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis
- ACS Med Chem Lett. 2020 Jun 10;11(7):1402-1409. doi: 10.1021/acsmedchemlett.0c00082.
- 1. Biocon Bristol Myers Squibb Research Center, Bangalore 560099, India.
- 2. Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
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 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.