Discovery of a Highly Potent, Selective, and Metabolically Stable   Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of   Systemic Inflammatory Response Syndrome

doi:10.1021/acs.jmedchem.6b01196

CORC > 北京大学 > 化学与分子工程学院

	Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
	Ren, Yan ; Su, Yaning ; Sun, Liming ; He, Sudan ; Meng, Lingjun ; Liao, Daohong ; Liu, Xiao ; Ma, Yongfen ; Liu, Chunyan ; Li, Sisi ; Ruan, Hanying ; Lei, Xiaoguang ; Wang, Xiaodong ; Zhang, Zhiyuan
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017
关键词	EXPERIMENTAL DISEASE-MODELS CELL-DEATH KINASE INHIBITORS INDUCED SHOCK NECROPTOSIS NECROSIS NECROSTATIN-1 SPECIFICITY INJURY ALPHA
DOI	10.1021/acs.jmedchem.6b01196
英文摘要	On the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNF alpha)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.; National Major Scientific and Technological Special Project for "Significant New Drugs Development" during the Twelfth Five-Year Plan Period from the Chinese Ministry of Science and Technology [2013ZX0950910]; SCI(E); ARTICLE; 3; 972-986; 60
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/475190]
专题	化学与分子工程学院
推荐引用方式 GB/T 7714	Ren, Yan,Su, Yaning,Sun, Liming,et al. Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017.
APA	Ren, Yan.,Su, Yaning.,Sun, Liming.,He, Sudan.,Meng, Lingjun.,...&Zhang, Zhiyuan.(2017).Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome.JOURNAL OF MEDICINAL CHEMISTRY.
MLA	Ren, Yan,et al."Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome".JOURNAL OF MEDICINAL CHEMISTRY (2017).