一种有效的选择性IRAK4抑制剂Edecesertib （GS-5718）的发现

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-15 DOI:10.1021/acs.jmedchem.5c00463

Stephen E Ammann,Jeromy J Cottell,Nathan E Wright,Matthew R Warr,Chelsea A Snyder,Elizabeth M Bacon,Gediminas Brizgys,Elbert Chin,Chienhung Chou,Angela Conway,Ryan A Dick,Ryan D Ferrao,Kimberly L Garrison,Angela Hammond,Eric B Lansdon,John O Link,Prasenjit Kumar Mukherjee,Bernard P Murray,Judy Mwangi,Marilyn S Ndukwe,Grace Y Park,Adrian P Serone,Kimberly Suekawa-Pirrone,Zheng-Yu Yang,Sheila M Zipfel,James G Taylor

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引用次数: 0

摘要

白细胞介素-1受体相关激酶4 （IRAK4）活性介导toll样和白细胞介素-1受体（TLR, IL-1R）下游的促炎信号和细胞因子产生。选择性IRAK4抑制剂作为炎症性疾病的潜在治疗方法引起了人们的兴趣。在此，我们报道了GS-5718 （edecesertib）的发现，这是一种有效的，选择性的，口服生物可利用的IRAK4抑制剂。这一努力的关键是在早期化合物遇到严重的hERG风险后，努力改善化学系列的特征。GS-5718在ind的临床前动物毒性研究中是安全且耐受性良好的，在小鼠NZB狼疮模型中证明了有效性，并且还证明了适合每天一次给药的人体药代动力学特性。Edecesertib目前正在进行狼疮治疗的临床评估。

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Discovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4.

Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery of GS-5718 (edecesertib), a potent, selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor were efforts undertaken to improve the chemical series' profile after a significant hERG liability was encountered for an early compound. GS-5718 was safe and well-tolerated in IND-enabling preclinical animal toxicity studies, demonstrated efficacy in a mouse NZB lupus model, and additionally demonstrated human pharmacokinetic properties suitable for once-daily administration. Edecesertib is currently under clinical evaluation for the treatment of lupus.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.