Chitase Lee

The synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity of tacrine (Cognex®) derivaties

Abstract Chlorosubstituted derivatives of tacrine (1), 1,4-methylenetacrine (2, and their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities are described. The most potent analogues are 6-chlorotacrine (1b) in AChE and 7-chlorotacrine (1c) in BChE inhibition.

Synthesis and evaluation of 2-aryl-4H-3,1-benzoxazin-4-ones as C1r serine protease inhibitors

Abstract A series of 2-aryl-4H-3,1-benzoxazin-4-ones have been synthesized and tested for inhibitory activity against C1r serine protease. Compounds were found that were equipotent and more selective than the reference compound FUT-175.

Synthesis and structure-activity relationships of 9-substituted acridines as endothelin-A receptor antagonists

Abstract Screening of a compound library against endothelin receptors (ETA and ETB) revealed PD 102566 (compound 1) as an ETA selective antagonist. Synthesis and structure-activity relationships (SAR) of a series of analogs are described.

PD 142676 (CI 1002), a novel anticholinesterase and muscarinic antagonist

Inhibition of brain acetylcholinesterase (AChE) can provide relief from the cognitive loss associated with Alzheimers disease (AD). However, unwanted peripheral side effects often limit the usefulness of the available anticholinesterases. Recently, we identified a dihydroquinazoline compound, PD 142676 (CI 1002) that is a potent anticholinesterase and a functional muscarinic antagonist at higher concentrations. Peripherally, PD 14276, unlike other anticholinesterases, inhibits gastrointestinal motility in rats, an effect consistent with its muscarinic antagonist properties. Centrally, the compound acts as a cholinomimetic. In rats, PD 142676, decreases core body temperature. It also increases neocortical arousal, as measured by quantitative electroencephalography, and cortical acetylcholine levels, measured by in vivo microdialysis. The compound improves the performance of C57/B10j mice in a water maze task and of aged rhesus monkeys in a delayed match-to-sample task involving short-term memory. The combined effect of AChE inhibition and muscarinic antagonism distinguishes PD 142676 from other anticholinesterases and may be useful in treating the cognitive dysfunction of AD and produce fewer peripheral side effects.

In Vitro and In Vivo Effects of a Dual Inhibitor of Acetylcholinesterase and Muscarinic Receptors, CI-1002

The observed loss of cholinergic innervation in the frontal cortex and hippocampus of Alzheimer’s Disease (AD) brains prompted the testing of centrally acting anticholinesterases to restore cholinergic tone and to produce cognitive improvement. The success of the anticholinesterase tacrine (THA, Cognex®) in benefitting the cognitive function of many individuals with AD (Knapp et al., 1994) validates this approach and encourages us to find even better compounds with which to treat the disease. Currently, a number of anticholinesterases, both reversible and irreversible inhibitors of acetylcholinesterase (AChE), are being studied for the treatment of AD (Jaen and Davis, 1993). However, many appear to be limited in their therapeutic usefulness by the production of peripheral cholinergic side-effects at the same drug concentrations that also improve cognitive performance (Kumar and Calache, 1991)). In an effort to overcome this limitation, we synthesized and characterized a series of substituted dihydroquinazolines that show anticholinesterase activity. The most potent of this series, CI-1002 (1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazoline),hasa potency similar to tacrine in inhibiting AChE, but unlike tacrine acts like an antagonist at muscarinic receptors at higher concentrations. The novelty of this dual action prompted us to characterize the in vitro and in vivo effects of CI-1002 to determine if it could be useful in the treatment of AD. Our data suggest that CI-1002 enhances performance of animals on cognitive tasks while producing few, if any, overt peripheral cholinergic side-effects. Thus, the combined effects of CI-1002, as an anticholinesterase and as a muscarinic antagonist, may improve the therapeutic potential of the compound.

CI-1002, a Novel Anticholinesterase and Muscarinic Antagonist

The “cholinergic deficit hypothesis” provided the first theoretical framework for developing rational, palliative treatments for the cognitive loss associated with Alzheimer’s Disease (AD). The hypothesis arose from the synthesis of several lines of evidence showing the importance of central cholinergic function to normal cognition, and the relationship between AD dementia and the loss of cholinergic innervation to the neocortex and hippocampus (for a review see Davis et al., 1993). The “hypothesis” led to the testing of agents to restore central cholinergic function. A variety of replacement therapies were tried including inhibitors of acetylcholinesterase (AChE) to increase brain levels of acetylcholine. Initial studies using the anticholinesterase physostigmine provided suggestive evidence that such an approach might be beneficial (for a review see Kumar and Calache, 1991). However, early clinical results with tacrine (THA, Cognex®) sparked the effort to evaluate thoroughly the efficacy of cholinesterase inhibitors in the treatment of AD.