82230-49-7Relevant articles and documents
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
, p. 972 - 986 (2017/02/19)
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 (TNFα)-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.
Elimination reactions of N-alkyl-N-chlorothenylamines promoted by MeONa-MeOH and Et2NH-MeCN. Effect of the β-aryl group on the imine-forming transition state
Pyun, Sang Yong,Lee, Dong Choon,Seung, Yoon Je,Cho, Bong Rae
, p. 5327 - 5330 (2007/10/03)
Elimination reactions of N-alkyl-N-chlorothenylamines 1-4 with MeONa-MeOH and Et2NH-MeCN have been studied kinetically. The elimination reactions are regiospecific, producing only the conjugated imines. The reactions are second order and exhibit substantial values of Hammett ρ and k H/kD, and an E2 mechanism is evident. The relative rates of elimination for Me/Et/i-Pr/i-Bu substituents are 1/0.5/0.2/0.02 with MeONa-MeOH and 1/0.4/0.2/0.06 with Et2NH-MeCN. The transition state structure changes toward more product-like as the base is changed from MeONa-MeOH to Et2NH-MeCN. Comparison with existing data reveals that the structure of the transition state is relatively insensitive to the β-aryl group variation.
