Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4

Zhulun Wang; Daqing Sun; Sheree Johnstone; Zhaodan Cao; Xiong Gao; Juan C Jaen; Jingqian Liu; Sarah Lively; Shichang Miao; Athena Sudom; Craig Tomooka; Nigel P C Walker; Matthew Wright; Xuelei Yan; Qiuping Ye; Jay P Powers

doi:10.1016/j.bmcl.2015.10.060

Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4

Bioorg Med Chem Lett. 2015 Dec 1;25(23):5546-50. doi: 10.1016/j.bmcl.2015.10.060. Epub 2015 Oct 23.

Authors

Affiliations

¹ Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: zwang@amgen.com.
² Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: daqingsun@yahoo.com.
³ Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.

PMID: 26526214
DOI: 10.1016/j.bmcl.2015.10.060

Abstract

In this Letter, we report the continued optimization of the N-acyl-2-aminobenzimidazole series, focusing in particular on the N-alkyl substituent and 5-position of the benzimidazole based on the binding mode and the early SAR. These efforts led to the discovery of 16, a highly potent, selective, and orally bioavailable inhibitor of IRAK-4.

Keywords: Inflammation; Interleukin-1 receptor-associate kinase-4; N-Acyl-2-aminobenzimidazole.

MeSH terms

Administration, Oral
Animals
Benzimidazoles / chemistry
Drug Discovery*
Enzyme Activation / drug effects
Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
Molecular Structure
Protein Binding / drug effects
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Rats
Structure-Activity Relationship

Substances

Benzimidazoles
Protein Kinase Inhibitors
2-aminobenzimidazole
Interleukin-1 Receptor-Associated Kinases