title: Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4.
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.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: zwang@amgen.com.
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: daqingsun@yahoo.com.
authors.forename: Daqing
authors.initials: D
authors.lastname: Sun
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sheree
authors.initials: S
authors.lastname: Johnstone
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Zhaodan
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Xiong
authors.initials: X
authors.lastname: Gao
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Jaen
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jingqian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lively
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Shichang
authors.initials: S
authors.lastname: Miao
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Tomooka
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Nigel P C
authors.initials: NP
authors.lastname: Walker
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Powers
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C027391:2-aminobenzimidazole; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Inflammation; Interleukin-1 receptor-associate kinase-4; N-Acyl-2-aminobenzimidazole