Synthesis and Evaluation of 5-Amino-5,6,7,8-tetrahydroquinolinones as Potential Agents for the Treatment of Alzheimer's Disease

Fink, David M.; Bores, Gina M.; Effland, Richard C.; Huger, Francis P.; Kurys, Barbara E.; Rush, Douglas K.; Selk, David E.

doi:10.1021/jm00018a025

Cited by 27 publications

(5 citation statements)

References 11 publications

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“…The ratio of donepezil IC 50 for BuChE to AChE from rodents and humans was found to be 1252:1 and 405:1, respectively [5,6]. This relative selectivity could be the reason for the low incidence of clinically relevant peripheral cholinergic side effects.…”

Section: Pharmacodynamicsmentioning

confidence: 96%

Donepezil in the treatment of patients with Alzheimer’s disease

Tsuno¹

2009

Expert Review of Neurotherapeutics

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Alzheimer's disease (AD) is the most common cause of dementia and is characterized by an insidious onset and slow deterioration in cognition, activities of daily living (ADL), mood stability and social functioning. The cholinesterase inhibitors (ChEIs), developed based on the cholinergic hypothesis, are currently considered to be the best established treatment for AD, although the significant advances in the symptomatic pharmacotherapy of AD may be followed by disease-modification treatments. Donepezil is a mixed competitive and noncompetitive acetylcholinesterase inhibitor that shows a relative selectivity for acetylcholinesterase inhibitor compared with butyrylcholinesterase. In many clinical trials of donepezil, beneficial effects on standard measures of cognitive function, ADL and behavior have been shown in patients with mild, moderate or severe AD. Although the pharmacological and phamacokinetic profiles of the currently available ChEIs have notable differences that may affect efficacy, the clinical significance of these differences remains hypothetical in the absence of large, randomized trials that compare the ChEIs with each other.

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Section: Pharmacodynamicsmentioning

confidence: 96%

Donepezil in the treatment of patients with Alzheimer’s disease

Tsuno¹

2009

Expert Review of Neurotherapeutics

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“…To get around this limitation, simpler analogs were designed and prepared. All of these possess the supposed pharmacophoric moiety of HupA: substituted 5-aminomethyl-2(1H)-pyridones 138, 225,231 substituted 5amino-5,6,7,8-tetrahydroquinolinones 139a-d, 140, 186,193,232 and 5-substituted aminoquinolinones 141. 186 The single ring analogs 142a-d 186 and several bridged ring analogs 143a-c 186,233 derived from HupA by the removal of the bridge and the opening of pyridone ring were also prepared (see Fig.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

The Lycopodium alkaloids

2004

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Lycopodium alkaloids are quinolizine, or pyridine and alpha-pyridone type alkaloids. Some Lycopodium alkaloids are potent inhibitors of acetylcholinesterase (AChE). Huperzine A (HupA) is reported to increase efficiency for learning and memory in animals, and it shows promise in the treatment of Alzheimer's disease (AD). 201 Lycopodium alkaloids from 54 species of Lycopodium (sensu lato) have been reported so far. This review is intended to to cover the chemical, pharmacological and clinical research on Lycopodium alkaloids reported in the literature from the spring of 1993 to August 2004. Structures of 81 new Lycopodium alkaloids are presented, classified and analyzed. The structural characters and biogenetic relationships of the four major Lycopodium alkaloid groups (lycopodine, lycodine, fawcettimine and miscellaneous) are discussed. Bioactivities of Lycopodium alkaloids, especially HupA, are summarized. In particular, the effect of HupA and other cholinesterase inhibitors (anti-AD drugs) on acetylcholine esterase (AChE) activity in the rat cortex and butylcholine esterase activity are compared. Structure-activity relationships and structure modifications of HupA and its analogs are described. Information on clinical trials with HupA and its derivative ZT-1 is presented. The state of HupA availability and recent advances in in vitro propagation of HupA producing plants are outlined. Finally, hypotheses about Lycopodium alkaloid biosynthetic pathways are discussed.

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“…From the synthetic point of view it is important to mention that 5,6,7,8-tetrahydro-2 H -1-benzopyran-2,5-diones can be transformed to the quinoline system by the action of some nitrogen-containing nucleophiles, such as ammonia, various amines, amino acids, hydrazine, and N , N -dimethylhydrazine. 1b, This transformation is in accordance with higher thermodynamic stability of quinolines in comparison with isomeric 5-hydrazono- or 5-imino-2 H -1-benzopyran-2-ones 3e…”

Section: Introductionmentioning

confidence: 94%

“…We investigated the possibility of transformation of some N -(5,6,7,8-tetrahydro-2,5-dioxo-2 H -1-benzopyran-3-yl)benzamides 4 with phenylhydrazine, various heterocyclic hydrazines, and hydrazides as nitrogen-containing nucleophiles at both positions of such a system, at the lactone ring and at 5-oxo group. By the application of already described reaction conditions, in absolute ethanol and in the presence of p -toluenesulfonic acid as a catalyst,3e we obtained the corresponding 5-hydrazonobenzopyrans in high yields …”

Section: Introductionmentioning

confidence: 96%