Bioorganic & Medicinal Chemistry Letters
Discovery of potent, selective, and orally bioavailable inhibitors
of interleukin-1 receptor-associate kinase-4
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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
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
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 bioavail-
able inhibitor of IRAK-4.
Received 16 July 2015
Revised 17 October 2015
Accepted 20 October 2015
Available online 23 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Interleukin-1 receptor-associate kinase-4
N-Acyl-2-aminobenzimidazole
Inflammation
Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a
ubiquitously expressed serine/threonine kinase and is responsible
for initiating signaling from Toll-like receptors (TLRs) and mem-
bers of the IL-1/18 receptor family. IRAK-4 and its IRAK isoforms
share a domain structure and activate similar signal transduction
of NF-kB and MAPK pathways.1–4 However, unlike the other IL-1
receptor-associated kinases (IRAK-1,1 IRAK-2,2 and IRAK-M3),
IRAK-4 requires its kinase activity to activate NF-kB.4 Endogenous
IRAK-4 interacts with IRAK-1 and TRAF6 in an IL-1-dependent
manner but is not redundant with IRAK-1, indicating that IRAK-4
may play a major role in the early signal transduction of Toll/IL-1
receptors. To this end, we found that mice with either IRAK-4
knockout or IRAK-4 targeted deletion had reductions in TLR and
IL-1 induced pro-inflammatory cytokines and were resistant to
induced joint inflammation in both antigen-induced arthritis
(AIA) and serum transfer-induced (K/BxN) arthritis models.5 These
results strongly suggest that IRAK-4 is indispensable for IL-1
signal transduction and its kinase activity is required for signal
transduction. Furthermore, human patients who lack full-length
IRAK-4 expression suffer from a compromised immune response.6
Therefore, selective inhibition of IRAK-4 has emerged as a potential
therapeutic strategy for the treatment of inflammatory pathologies
such as atherosclerosis.7–12
Previously, we reported the identification of a novel series of
N-acyl-2-aminobenzimidazole IRAK-4 inhibitors exemplified by 1
(Fig. 1) from initial optimization efforts on an HTS lead.11
Compound 1 inhibited both IRAK-4 and its isoform IRAK-1 in a
chemiluminescent ELISA assay,13 with an IC50 of 0.15
l
M and
0.9
lM, respectively. The early structure–activity relationship
(SAR) studies in this series13 identified the pharmacophore
required for IRAK inhibition: (a) the secondary amide connection
between the two aryl groups is favorable for potency as alkylation
of the amide led to a substantial loss of activity, (b) both 3-nitro
and 3-trifluoromethyl groups at the benzamide were beneficial
for activity against IRAK-4, and (c) substitutions on the nitrogen
and 5-positions of the benzimidazole significantly improved
IRAK-4 inhibition.
Binding affinity of 1 to IRAK-4 can be explained by key interac-
tions of three hydrogen bonds and van der Waals interactions,
which were observed in the co-crystal structure of 1 with IRAK-4
(Fig. 2).14 As an ATP-site inhibitor, compound 1 makes a typical
hinge hydrogen bond with the amide carbonyl accepting a hydro-
gen bond from the backbone amide of Met265. The nitro group
forms a weak hydrogen bond with the side-chain NH+3 of catalytic
Abbreviations: MeCN, acetonitrile; CL, clearance; Dess–Martin periodinane,
1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DIBALH, diisobutyl-
aluminum hydride; DMF, N,N-dimethylformamide; EtOAc, ethyl acetate; HBTU, N,N,
N0,N0-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate; HOBT,
hydroxybenzotriazole; NMM, N-methylmorpholine; THF, tetrahydrofuran.
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Corresponding authors. Tel.: +1 650 244 2446; fax: +1 650 837 9427 (Z.W.);
tel.: +1 650 619 1742; fax: +1 650 837 9427 (D.S.).
(D. Sun).
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.