Youichi Iimura

Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimers disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimers patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimers drugs in various phases of clinical development.

Conformational analyses and molecular-shape comparisons of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase. [Erratum to document cited in CA116(11):98893e]

Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring.