title: Discovery of novel 2,6-disubstituted pyridazinone derivatives as acetylcholinesterase inhibitors.
abstract: 2,6-Disubstituted pyridazinone 4 was identified by HTS as a novel acetylcholinesterase (AChE) inhibitor. Under SAR development, compound 17e stood out as displaying high AChE inhibitory activity and AChE/butyrylcholinesterase (BuChE) selectivity in vitro. Docking studies revealed that 17e might interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) simultaneously. Based on this novel binding information, 6-ortho-tolylamino and N-ethyl-N-isopropylacetamide substituted piperidine were disclosed as new PAS and CAS binders.
authors: State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors: Weiqiang
authors: W
authors: Xing
authors: Yan
authors: Y
authors: Fu
authors: Zhangxing
authors: Z
authors: Shi
authors: Dong
authors: D
authors: Lu
authors: Haiyan
authors: H
authors: Zhang
authors: Youhong
authors: Y
authors: Hu
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D001667:Binding, Competitive; D055162:Biocatalysis / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011724:Pyridazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D010880:Piperidines; D011724:Pyridazines; C032727:piperidine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase