Design, synthesis, and structure-activity relationship of novel RIPK2 inhibitors.

Autor: Wu S; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China., Xu L; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China., Wang X; CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China., Yang Q; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China., Wang J; CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China., He S; CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China; State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China. Electronic address: hesd@ism.pumc.edu.cn., Zhang X; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: xiaohuzhang@suda.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Nov 01; Vol. 75, pp. 128968. Date of Electronic Publication: 2022 Sep 02.
DOI: 10.1016/j.bmcl.2022.128968
Abstrakt: The NOD1/2 (nucleotide-binding oligomerization domain-containing protein 1/2) signaling pathways are involved in innate immune control and host defense. NOD dysfunction can result in a variety of autoimmune disorders. NOD-induced generation of inflammatory cytokines is mediated by receptor-interacting protein kinase 2 (RIPK2), which has been considered as a promising therapeutic target. Herein, we disclose the design, synthesis, and SAR study of a series of RIPK2 inhibitors. The lead compound 17 displayed a high affinity for RIPK2 (K d  = 5.9 nM) and was capable of inhibiting RIPK2 kinase function in an ADP-Glo assay. In vitro DMPK studies showed that compound 17 had good metabolic stability and no CYP inhibition. Compound 17 effectively suppressed inflammatory cytokine production in both cells and animal model.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022. Published by Elsevier Ltd.)
Databáze: MEDLINE
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