IRAK-4 inhibitors. Part 1: A series of amides

Buckley, George M.; Gowers, Lewis; Higueruelo, Alícia P.; Jenkins, Kerry; Mack, Stephen R.; Morgan, Trevor; Parry, David M.; Pitt, William R.; Rausch, Oliver; Richard, Marianna D.; Sabin, Verity; Fraser, Joanne L.

doi:10.1016/j.bmcl.2008.04.058

Cited by 34 publications

(31 citation statements)

References 11 publications

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“…A few novel series of potent IRAK-4 kinase inhibitors have been described, including amino-benzimidazoles [59], thiazole or pyridine amides [60], imidazo[1,2- a ]pyridines [61, 62], imidazo[1,2- b ]pyridazines, and benzimidazole-indazoles [58, 64]. The chemical structures of some representative inhibitors from these series are shown in Fig.…”

Section: Irak-4 Inhibitor Developmentmentioning

confidence: 99%

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IRAK-4 Inhibitors for Inflammation

Wang

Wesche²,

Stevens³

et al. 2009

CTMC

125

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Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. In this article, we review the biological function of IRAK-4, the structural characteristics of the kinase domain, and the development of small molecule inhibitors targeting the kinase activity. We also review the key pharmacophores required for several classes of inhibitors as well as important features for optimal protein/inhibitor interactions. Lastly, we summarize how these insights can be translated into strategies to develop potent IRAK-4 inhibitors with desired properties as new anti-inflammatory therapeutic agents.

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Section: Irak-4 Inhibitor Developmentmentioning

confidence: 99%

“…9 ) was identified as an initial hit from screening a small molecule library against IRAK-4 [60]. SAR studies around 9 carried out by Buckley et al .…”

Section: Irak-4 Inhibitor Developmentmentioning

confidence: 99%

IRAK-4 Inhibitors for Inflammation

Wang

Wesche²,

Stevens³

et al. 2009

CTMC

125

View full text Add to dashboard Cite

show abstract

“…Later in 2008, George and co-workers explored the SAR around thiazole amide nucleus for IRAK-4 inhibition [110]. The phenyl ring attached to the NH of amide linker is favorable for substitutions.…”

Section: Amide Derivativesmentioning

confidence: 99%

Interleukin-1 receptor associated kinase inhibitors: Potential therapeutic agents for inflammatory- and immune-related disorders

Bahia

Kaur

Silakari

et al. 2015

Cellular Signalling

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“…In this study, the data set of 65 amides and imidazo [1,2-α] pyridines were collected as IRAK-4 inhibitors, as previously reported [6][7][8]. The inhibitory activity values are expressed as the half maximal inhibitory concentration (IC 50 ).…”

Section: Data Setmentioning

confidence: 99%

“…Recently, a novel series of amides and imidazo [1,2-α] pyridines as inhibitors of IRAK-4 have been reported by Buckley and co-workers. [6][7][8].…”

Section: Introductionmentioning

confidence: 99%