Alzheimer medicine?

Question

I need details about how the discovery was made of certain drug drug. Specifically, was it discovered in Japan? Did they hypothesize the structure based on the Ache, or did they use a lead from a plant? below are more details - the generic name is donepezil hydrochloride

also known as Aricept, chemical name: (?±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride (E2020)

Answer 1

It does look like it was discovered in Japan. I found this abstract which has all Japanese names on it. It doesn't sound like it came from a plant.
Here's the abstract and I don't pretend to understand it at all:
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The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).

Answer 2

Drug discovery now works via mass screening of small molecules connected to a structural database. Each of the molecules interacts with a target of interest, and light emission changes are detected by computer. Once a few candidates are out, x-ray crystallography informs more about the structure, and possible modification are made on a software simulation level from there, only then comes weblab experimentation.

BTW: there are major items in the drug pipleine for ALZ ..keep
your thumbs crossed, just in clinical trials....

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