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Bioorg Med Chem Lett. 2015 Nov 15;25(22):5384-8. doi: 10.1016/j.bmcl.2015.09.028. Epub 2015 Sep 11.

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

Author information

1
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States. Electronic address: jongwon_lim@merck.com.
2
Department of Chemistry Modeling and Informatics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
3
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
4
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
5
Department of In Vitro Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
6
Department of Immunology, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.

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.

KEYWORDS:

IRAK4; Kinase inhibitor; N-(1H-Pyrazol-4-yl)carboxamide; SAR; Serine–threonine kinase

PMID:
26403930
DOI:
10.1016/j.bmcl.2015.09.028
[Indexed for MEDLINE]

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