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Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications.

Abstract：

:IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Lim J,Altman MD,Baker J,Brubaker JD,Chen H,Chen Y,Kleinschek MA,Li C,Liu D,Maclean JK,Mulrooney EF,Presland J,Rakhilina L,Smith GF,Yang R

doi

10.1016/j.bmcl.2015.09.028

subject

Has Abstract

pub_date

2015-11-15 00:00:00

pages

5384-8

issue

22

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)30062-7

journal_volume

25

pub_type

杂志文章

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