Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Lim, Jongwon; Altman, Michael D.; Baker, James; Brubaker, Jason D.; Chen, Hongmin; Chen, Yiping; Kleinschek, Melanie A.; Li, Chaomin; Liu, Duan; Maclean, John K.F.; Mulrooney, Erin F.; Presland, Jeremy; Rakhilina, Larissa; Smith, Graham F.; Yang, Ruojing
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5384
• Page End: 5388
• Publication Date: 2015-11-15
• Subjects: IRAK4 -- N-(1H-Pyrazol-4-yl)carboxamide -- SAR -- Serine–threonine kinase -- Kinase inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.09.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 -(1 H -pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino- N -(1 H -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 c Log D led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.