Novel Dual binding inhibitor of Acetylcholinesterase for the treatment of Alzheimer’s disease

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the progressive decline in cognitive functions, primarily memory, and the development of behavioral changes. The risk of AD significantly increases with age, while the World Health Organization (WHO) considers AD as one of the main causes of disability in the elderly.

Alzheimer type dementia is accompanied by the degeneration of cholinergic neurons in the brain that release the neurotransmitter acetylcholine. Therefore, prolongation of the lifetime of acetylcholine by partial inhibition of the acetylcholine degrading enzyme (acetylcholinesterase; AChE) in patients in the early stages of the disease has a positive symptomatic effect. In addition, AD is characterized by the excessive production and accumulation of β-amyloid peptide (Aβ) in the brain, which plays an important role in the pathogenesis of AD. Aβ is an oligopeptide consisting of 25-42 amino acid residues, which is formed by the cleavage of the amyloid precursor protein by beta and gamma secretase enzymes. It polymerizes to form long insoluble febrile complexes (Aβс) that are a key component of β-amyloid (senile) plaques formed in the brain of AD patients.

Scheme of amyloidogenic pathway for Alzheimer diseases

Currently approved therapeutic drugs for AD inhibit acetylcholinesterase activity, or inhibit Aβc production/accumulation or aggregation in the brain.

AVVA Pharmaceuticals has developed a novel small molecule (C29) that has the ability to inhibit activity of AChE and can prevent aggregation of Aβ in the brain.

Chemical structure and structure activity relationship of C29. А. Chemical structure of molecule with highlighted active parts of molecule responsible for binding with acetylcholinesterase. B. Scheme of C29 interaction with acetylcholinesterase active site.

Results Of Discovery Studies With C29

C29 and Dpz inhibitory activity of Aß40 aggregation
induced by AChE in vitro

C29 5 mg/kg

Pharmacokinetics of C29 in brain and blood after single orally treated rats

control_tg+

Control (Tg+)

Donepezil

Donepezil 5 mg/kg

Amyloid plaques in the brain of transgenic mice (B6C3-Tg(APP695swe/PSEN1) after 14 days treatment with C29 and Donepezil

*** the difference with the control is statistically significant at p≤0.001

Comparison with control is performed by two-side Mann-Whitney test.

Aβ accumulation in brain of B6C3-Tg(APP695swe/PSEN1) mice during 14 days treatment with C29

Inventor’s Team

konst

Konstantin A. Petrov,
PhD

Head of International Research and Innovation Center for Neurochemistry and Pharmacology at Arbuzov Institute of Organic and Physical Chemistry of FRC Kazan Scientific Center of RAS

vjacheslav

Vyacheslav E. Semenov, PhD

Doctor of Science (Chemistry), Assistant professor
Head of Laboratory of Chemistry of Nucleotide Bases at Arbuzov Institute of Organic and Physical Chemistry of FRC Kazan Scientific Center of RAS