Treating Alzheimer’s Disease by Acetylcholinesterase Inhibition

Treating Alzheimer’s Disease by Acetylcholinesterase Inhibition Kristina Nivus

Alzheimer’s Disease • Loss of memory and cognitive functioning over several years, involving mild, moderate and severe stages • Cognitive signs and symptoms caused by plaques and tangles in the brain • These arise from overactivity of acetylcholinesterase (AChE) which drastically lowers cortical acetylcholine levels • Aricept was developed to be AChE specific, have reversible binding and have a pharmacokinetic profile that allows for once daily dosing

AChE Overdrive

AChE Structure Suh et al. Therapeutic Agents for Alzheimer’s Disease.

Aricept • (R, S)-1-benzyl-4-[(5, 6-dimethoxy-1-indanone)-2-yl]-methyl-piperidine hydrochloride Sippl et al. Structure-based 3D QSAR & Design of Novel Acetylcholinesterase Inhibitors.

Aricept • Bioavailabilty: 100% • Easily crosses the blood-brain barrier • Half-life: 70 hours • Available as serum or orally disintegrating tablets

Biological Target • Aricept inhibits AChE’s ability to hydrolyze acetylcholine into choline and acetic acid • Binds to Glu327, His440, Ser200 residues in hydrophobic gorge • Substituted phenyl helps position molecule in gorge • Modified piperidine ring creates π-π interactions that stabilize binding • Indanone ring helps create electrostatic interactions

AChE Inhibition Suh et al. Therapeutic Agents for Alzheimer’s Disease.

Importance to Human Health • Selectivity for acetylcholinesterase • Lack of adverse effects on patient population

Timeline of Development • AChE structure elucidated using • x-ray structure analyses, x-ray crystal structures • Combined docking analyses • 2D and 3D QSAR • AChE binding determined using small, non-specific inhibitors

Timeline of Development • Aricept structure developed from inhibitors that had the highest binding constants • X-ray structure analyses, x-ray crystal structures • Combined docking analyses • 2D and 3D QSAR • Molecular modeling

FDA Approval Process • Approved for mild and moderate stages of Alzheimer’s in November 1996 • Approved for severe stages of Alzheimer’s in 2006

Preclincal & Phase I Trials • Preclinical Trials • Aricpet has greater specificity for brain tissue and is more selective for AChE than physostigimine or tacrine • Phase I Clinical Trials • Aricpet has greater specificity for brain tissue than other AChE inhibitors similar in structure

Phase II Trials • 5 mg of Aricept provided significant global and cognitive improvements • Benefits were provided without peripheral adverse effects, laboratory test abnormalities or hepatoxic effects • Evaluated using the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Clinician’s Interview Based on Impression of Change (CIBIC)

Phase III Trials • Phase III consists of many trials • Two main trials considered by the FDA • Fifteen week study (twelve week active treatment, three week washout) and thirty week study (twenty four week active treatment and six week washout)

Phase III Trials Cont. • All studies were randomized, double-blind, placebo-controlled, parallel-group, dual-outcome assessed trials • Outcomes assessed with Alzheimer’s Disease Assessment Scale and Clinician’s Interview Based on Impression of Change

Mean change from baseline in ADAS-cog score for 5 mg and 10 mg Rogers et al. A 24 Week Double-Blind, Placebo-Controlled Trial of Donepezil in Patients with Alzheimer’s Disease.

Mean CIBIC plus score Rogers et al. A 24 Week Double-Blind, Placebo-Controlled Trial of Donepezil in Patients with Alzheimer’s Disease.

Conclusion • Aricept is approved for all stages of Alzheimer’s disease and provides the most side effect-free, effective treatment of Alzheimer’s symptoms • There is currently no treatment for the plaques and tangles • Aricept can halt the progression of Alzheimer’s and improve the quality of life for Alzheimer’s patients for a number of years before their disease begins to progress again

Treating Alzheimer’s Disease by Acetylcholinesterase Inhibition