Current Medicinal Chemistry - Volume 7, Issue 3, 2000

Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents useful for the treatment of Alzheimers disease, glaucoma, myasthenia gravis and for the recovery of neuromuscular block in surgery. To rationalize the structural requirements of AChE inhibitors we attempt to derive a coherent AChE-inhibitor recognition pattern based on literature data of molecular modelling and quantitative structure-activity relationship (QSAR) analyses. These data are summarised from nearly all therapeutically important chemical classes of reversible AChE inhibitors, e.g., derivatives of physostigmine, tacrine, donepezil and huperzine A. Interactions observed from X-ray crystallography between these inhibitors and AChE have also been incorporated and compared with modelling and QSAR results. It is concluded that hydrophobicity and the presence of an ionizable nitrogen are the pre-requisites for the inhibitors to interact with AChE. However the mode of interaction i.e., the 3-dimensional (3D) positioning of the inhibitor in the active site of the enzyme varies among different chemical classes. It is also recognised that water molecules play crucial roles in defining these different 3D positioning. The information on AChE-inhibitor interactions provided should be useful for future discovery of new chemical classes of AChE inhibitors, especially from De Novo design and hybrid construction.

Abstract: Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with a-cyanoketones, and reactions involving anilines and cyclic b-ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase.

A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer 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.

A series of benzylamino inhibitors of acetylcholinesterase (AChE) have been designed based on a working hypothesis of the enzymes active site. These compounds were tested for their inhibitory activities on AChE and potent inhibitors were further evaluated in terms of central selectivity. These studies led to a discovery of 3-(1-(phenylmethyl)-4-piperidinyl)-1-( 2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147). Pharmacokinetic study has shown that the compound has high central selectivity, as demonstrated by rapid elimination from plasma and long-term existence in the brain. As a consequence, TAK-147 ameliorates impairments of learning and memory in various animal models without producing peripheral side effects. TAK-147 also activates the monoaminergic systems and energy metabolism. Furthermore, TAK-147 was revealed to have NGF-like neurotrophic activity on central cholinergic neurons at concentrations where it inhibits AChE activity. Therefore, TAK-147 is expected not only to ameliorate the clinical symptoms in Alzheimers disease via AChE inhibition but to prevent or slow the progression of the disease via its neurotrophic action. TAK-147 is now under clinical trial as a therapeutic drug for Alzheimers disease. This article reviews design and structure-activity relationships of TAK-147 and related compounds. Preclinical pharmacology of TAK-147 is also summarized.

HupA is a potent, reversible and selective inhibitor of AChE with a rapid absorption and penetration into the brain in animal tests. It exhibits memory-enhancing activities in animal and clinical trials. Compared to tacrine and donepezil, HupA possesses a longer duration of action and higher therapeutic index, and the peripheral cholinergic side effects are minimal at therapeutic doses. This review article deals with a comprehensive survey of the progress in chemical and pharmacological studies of HupA including the isolation and structure elucidation, pharmacological actions, total synthesis, SAR studies and the future development of HupA.Recently, it has been reported that HupA could reduce neuronal cell death caused by glutamate. The dual bio-activities of HupA would further enhance its value and potentiality as the therapeutic agent for Alzheimers disease.