Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

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• 作者：Jongwon Lim ; Michael D. Altman ; James Baker ; Jason D. Brubaker ; Hongmin Chen ; Yiping Chen ; Thierry Fischmann ; Craig Gibeau ; Melanie A. Kleinschek ; Erica Leccese ; Charles Lesburg ; John K. F. Maclean ; Lily Y. Moy ; Erin F. Mulrooney ; Jeremy Presland ; Larissa Rakhilina ; Graham F. Smith ; Dietrich Steinhuebel ; Ruojing Yang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：683-688
• 全文大小：316K
• ISSN：1948-5875

文摘

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.