Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine, and related derivatives

Abstract

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.

Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program

“…Three possibilities are therefore conceivable for this molecule: (i) that E2020 may bind to only one site and the other one is an artifact; (ii) that it binds to one site under some conditions and to the other site under other conditions; and (iii) that it switches among these two sites. The first possibility is, however, rendered unlikely by the fact that analog 6 [16] is more potent in the inhibition of AChE than analog 7 [16]. The increased inhibitory potency shown by 6 is compatible with the notion that 6 forms one more hydrogen bond to AChE (Fig.…”

Donepezil Improves Cognition and Global Function in Alzheimer Disease<subtitle>A 15-Week, Double-blind, Placebo-Controlled Study</subtitle>

“…A diagnosis of probable AD was required to be consistent with the National Institute of Neurological and Communicative Disorders and StrokeAlzheimer's Disease and Related Disorders Association criteria 16 and the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition categories 290.00 or 290. 10. 17 The patients had mild to moderately severe disease as defined by Mini-Mental State Examination (MMSE) 18 scores of 10 to 26, and screening and baseline Clinical Dementia Rating (CDR) scores of 1 or 2.…”

“…In addition, donepezil also has a longer duration of inhibitory action than either of these agents. 7,10 As a consequence of this high selectivity and specificity, donepezil should produce fewer peripheral cholinomimetic-induced adverse effects at effective doses. Indeed, in a phase 2 clinical trial, 5 mg of donepezil hydrochloride was shown not only to provide significant clinical improvements in cognitive and global function in patients with mild to moderately severe AD, but also these benefits were obtained without peripheral cholinergic adverse events, laboratory test abnormalities, or hepatotoxic effects.…”

Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

“…On the basis of these findings, we synthesized benzamide derivatives. We later on discovered that benzylsulfonyl derivative (compound 4) was the most potent AChE inhibitor with an anti-AChE activity 21,000-fold greater compared to the seed compound (26,32,33) (Fig. 4).…”