WK4: AD - MEDCHEM

What is the key requirement for Alzheimer's drugs to work?

They must cross the BBB to enter the CNS

What type of chemical group cannot cross the BBB?

Quaternary nitrogen (positively charged, N with 4 bonds)

Which Alzheimer's drug was licensed in 1997 as the 2nd approved drug?

Donepezil

What company developed donepezil?

Esai Ltd

What was donepezil originally synthesised for?

Anti-arterial sclerosis (had poor activity: IC50 12.6 μM)

What structural change gave a huge increase in activity for donepezil?

Switching from piperazine to piperidine

What structural change further increased activity for donepezil?

Switching ether to bioisosteric amide (amide can form H-bonds)

What derivative gave a 21,000-fold increase in activity?

Benzylsulfonyl derivative (but had poor bioavailability)

What is the IC50 of donepezil?

6.7 nM (very potent)

How long does donepezil's efficacy last?

70 hours

Is donepezil selective for AChE or BuChE?

Highly selective for AChE

What type of inhibition does donepezil use?

Reversible, non-covalent inhibition

What binding interactions does donepezil use?

π-π stacking with tryptophan, H-bonds with phenylalanine and tyrosine (water-mediated)

What is the natural source of galantamine?

Bulbs of snowdrops and daffodils

When was galantamine licensed?

2001

What additional property does galantamine have?

Positive allosteric modulator at nicotinic receptors

What was the lead compound for the carbamate class of drugs?

Physostigmine (natural product)

What is the mechanism of carbamate AChE inhibitors?

Carbamoylation of AChE → stable carbamoyl-enzyme intermediate

How is the carbamoyl-enzyme intermediate stabilised?

Resonance from the nitrogen lone pair

How much slower is hydrolysis of physostigmine compared to acetylcholine?

40 million times slower

What does "pseudo-irreversible" mean for rivastigmine?

Enzyme inhibition persists much longer than the drug is present in plasma

What is the half-life of rivastigmine?

Approximately 1 hour

How long does rivastigmine's inhibition persist?

Approximately 24 hours

Is rivastigmine selective for AChE?

No – it is non-selective (inhibits both AChE and BuChE)

Why does rivastigmine cross the BBB easily?

It has no formal positive charge

What was memantine first investigated as?

An antidiabetic drug (wasn't effective enough)

How was memantine's NMDA antagonist activity discovered?

During clinical trials for dementia

When was memantine approved?

2003

What type of NMDA antagonist is memantine?

Uncompetitive antagonist

What does memantine prevent?

Excess glutamate binding (excitotoxicity)

Which AChE inhibitor is a natural product?

Galantamine (from snowdrops)

Which AChE inhibitor is a carbamate?

Rivastigmine

Which AChE inhibitors are non-covalent and reversible?

Donepezil and galantamine