40478-49-7Relevant articles and documents
Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
Zhou, Yu,Fu, Yan,Yin, Wanchao,Li, Jian,Wang, Wei,Bai, Fang,Xu, Shengtao,Gong, Qi,Peng, Tao,Hong, Yu,Zhang, Dong,Zhang, Dan,Liu, Qiufeng,Xu, Yechun,Xu, H. Eric,Zhang, Haiyan,Jiang, Hualiang,Liu, Hong
, p. 1844 - 1855 (2021/03/01)
The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
Copper-Catalyzed Oxidative Benzylic C(sp3)?H Cyclization for the Synthesis of β-Lactams
Nozawa-Kumada, Kanako,Saga, Satoshi,Matsuzawa, Yuta,Hayashi, Masahito,Shigeno, Masanori,Kondo, Yoshinori
supporting information, p. 4496 - 4499 (2020/04/10)
β-Lactams are important structural motifs because of their ubiquity in natural products and pharmaceuticals. We report herein a Cu-catalyzed intramolecular oxidative C(sp3)?H amidation for the synthesis of β-lactams using tBuOOtBu. This method
GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists derived from 3-benzazepines: Synthesis and pharmacological evaluation of benzo[7]annulen-7-amines
Benner, Andre,Bonifazi, Alessandro,Shirataki, Chikako,Temme, Louisa,Schepmann, Dirk,Quaglia, Wilma,Shoji, Osami,Watanabe, Yoshihito,Daniliuc, Constantin,Wuensch, Bernhard
, p. 741 - 751 (2014/05/06)
Given their high neuroprotective potential, ligands that block GluN2B-containing N-methyl-D-aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neurona
