1-杂芳基-3-(1-苄基-4-哌啶基)丙-1-酮衍生物作为强效、选择性乙酰胆碱酯酶抑制剂的设计与合成

Design and synthesis of 1-heteroaryl-3-(1-benzyl-4-piperidinyl)propan-1-one derivatives as potent, selective acetylcholinesterase inhibitors.

作者信息

Nagel A A, Liston D R, Jung S, Mahar M, Vincent L A, Chapin D, Chen Y L, Hubbard S, Ives J L, Jones S B

机构信息

Department of Medicinal Chemistry, Pfizer Inc., Groton, Connecticut 06340, USA.

出版信息

J Med Chem. 1995 Mar 31;38(7):1084-9. doi: 10.1021/jm00007a005.

DOI:10.1021/jm00007a005

PMID:7707311

Abstract

Herein is described the synthesis and structure--activity relationship of a novel series of aromatic and heteroaromatic 3-(1-benzyl-4-piperidinyl)propan-1-one derivatives that display potent and selective inhibition of the enzyme acetylcholinesterase (AChE). 1-(2-Methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)propan-1-one hydrochloride, 6d, is one of the most active compounds within this series exhibiting an IC50 for the inhibition of the AChE enzyme equal to 6.8 nM. Compound 6d has shown a dose-dependent elevation of total acetylcholine (ACh) levels in the mouse forebrain with an oral ED50 = 9.8 mg/kg. In addition, in vivo microdialysis experiments in the rat demonstrate that 6d increases extracellular ACh (100% over basal) 1-3 h postdose with an oral ED50 = 4.8 mg/kg.

摘要

本文描述了一系列新型芳香族和杂芳香族3-(1-苄基-4-哌啶基)丙-1-酮衍生物的合成及其构效关系，这些衍生物对乙酰胆碱酯酶（AChE）具有强效和选择性抑制作用。1-(2-甲基-6-苯并噻唑基)-3-(N-苄基-4-哌啶基)丙-1-酮盐酸盐（6d）是该系列中活性最强的化合物之一，其对AChE酶抑制作用的IC50等于6.8 nM。化合物6d在小鼠前脑中显示出总乙酰胆碱（ACh）水平的剂量依赖性升高，口服ED50 = 9.8 mg/kg。此外，在大鼠体内进行的微透析实验表明，6d在给药后1 - 3小时可使细胞外ACh增加（比基础水平高100%），口服ED50 = 4.8 mg/kg。