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）

引用 6|浏览17

暂无评分

摘要

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 with improved potency and selectivity. Additionally demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective , which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

查看译文

关键词

IRAK4,kinase,lupus,TLR,psoriasis

AI 理解论文

溯源树

样例

生成溯源树，研究论文发展脉络

Chat Paper

正在生成论文摘要