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

Satheesh Nair, Sreekantha Ratna Kumar, Venkatram Reddy Paidi, Ramesh Sistla, Durgarao Kantheti, Subba Rao Polimera, Soodamani Thangavel, Amrita Jha Mukherjee, Mitalee Das, Rajeev S. Bhide, William J. Pitts, Natesan Murugesan, Shailesh Dudhgoankar, Jignesh Nagar, Siva Subramani, Debarati Mazumder, Julie A. Carman, Deborah A. Holloway, Xin Li, Mark P. Fereshteh, Stefan Ruepp, Kamalavenkatesh Palanisamy, T. Thanga Mariappan, Srinivas Maddi, Ajay Saxena, Paul Elzinga, Anjaneya Chimalakonda, Qian Ruan, Kaushik Ghosh, Sucharita Bose, John Sack, Chunhong Yan, Susan E. Kiefer, Dianlin Xie, John A. Newitt, S. Pon Saravanakumar, Richard A. Rampulla, Joel C. Barrish, Percy H. Carter, John Hynes

ACS MEDICINAL CHEMISTRY LETTERS（2020）

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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 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.

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Key words

IRAK4,kinase,lupus,TLR,psoriasis

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