Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives
| Autor: | Kiyomi Yamatsu, Hiroyuki Sugumi, Yoshiharu Yamanishi, Norio Karibe, Atsushi Sasaki, Yutaka Tsuchiya, Kunizo Higurashi, Yoichi Iimura, Hachiro Sugimoto, Shin Araki |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Hydrochloride Stereochemistry Phthalimides chemistry.chemical_compound Structure-Activity Relationship Piperidines Amide Drug Discovery Structure–activity relationship Phenyl group Animals Rats Wistar Imide biology Bicyclic molecule Molecular Structure Brain Rats chemistry Enzyme inhibitor Butyrylcholinesterase biology.protein Acetylcholinesterase Molecular Medicine Piperidine Cholinesterase Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 35(24) |
| ISSN: | 0022-2623 |
| Popis: | Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain. |
| Databáze: | OpenAIRE |
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