A MAJOR APPROACH- 2-CHLOROPYRIDINE-5-TRIFLUOROMETHYL DERIVATIVE AS ANTIAMNESIC AGENTS

Pharma Admission

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Current FDA-approved Alzheimer drugs support this communication process through two different mechanisms:
1) Cholinesterase inhibitors work by slowing down the disease activity that breaks down a key neurotransmitter. Donepezil, galantamine, rivastigmine and tacrine are cholinesterase inhibitors.

2) Memantine, the fifth Alzheimer drug, is an NMDA (N-methyl-D-aspartate) receptor antagonist, which works by regulating the activity of glutamate, a chemical messenger involved in learning and memory.

Memantine protects brain cells against excess glutamate, a chemical messenger released in large amounts by cells damaged by Alzheimer's disease and other neurological disorders. Attachment of glutamate to cell surface "docking sites" called NMDA receptors permits calcium to flow freely into the cell. Over time, this leads to chronic over exposure to calcium, which can speed up cell damage. Memantine prevents this destructive chain of events by partially blocking the NMDA receptors.

On average, the five approved Alzheimer drugs are effective for about six to 12 months for about half of the individuals who take them.

2. REVIEW OF LITERATURE
Alzheimer’s disease (AD) is an age-related neurodegenerative process characterized by a progressive loss of cognitive abilities, such as memory, language skills, disorientation, attention, and depression.11

Although the etiology of AD is still poorly understood, several factors such as
*  amyloid-β (Aβ)deposits,
*  ς-protein aggregation,
*  oxidative stress or
*  Low levels of acetylcholine are main factor in the pathology of the disease.

In spite of the lot of research effort, an efficient strategy for designing new drugs for the treatment of AD is still lacking.


Factors involved in the pathogenesis of Alzheimer’s disease (AD). Abbreviations: Ab, b-amyloid; APP, amyloid precursor protein; PS1, presenilin 1.12

2.1 Till the research which has been done or undergoing includes-2.1.1. Acetyl cholinesterase (AChE) inhibitors13-
The cholinergic theory suggests that the selective loss of cholinergic neurons in AD results in a deficiency of acetylcholine (ACh) in specific regions of the brain that mediate learning and memory functions. Consequently, three acetyl cholinesterase (AChE) inhibitors have been approved for commercial use.

Thus, donepezil, rivastigmine, and galanthamine improve AD symptoms by inhibiting AChE, (the enzyme responsible for the hydrolysis of ACh, thereby raising the levels of ACh in the synaptic cleft.


2.1.2 β-secretase inhibitors15
The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer’s disease.The pathological hallmarks of AD include the aggregation and extracellular deposition of β-amyloid peptide (Aβ), which leads to plaque formation, and the abnormal hyperphosphorylation of tau protein, which leads to the intracellular formation of neurofibrillary tangles.


Plaques and tangles in the cerebral cortex in Alzheimer’s disease

β-amyloid deposits are predominately aggregates of the Aβ peptides (Aβ, 39– 43 residues) resulting from the endoproteolysis of the amyloid precursor protein (APP).

These peptide fragments result from the sequential cleavage of APP, first at the N-terminus by β-secretase enzyme (β-site APP cleaving enzyme, BACE1), followed at the C-terminus by one or more γ-secretase complexes (intramembrane aspartyl proteases), as part of the β-amyloidogenic pathway.

In the pathogenesis of the disease Aβ plays a central role.

Thus, processes that limit Aβ production and deposition by preventing formation, inhibiting aggregation, and/or enhancing clearance may offer effective treatments for AD.

Since β-secretase mediated cleavage of APP is the first and rate-limiting step of the amyloidogenic processing pathway, BACE1 inhibition is considered a prominent therapeutic target for treating AD by diminishing Aβ peptide formation in AD patients.

Example- pyrrolyl 2- aminopyridines as BACE1 inhibitors.


2.1.3. γ-secratase inhibitor17-
In AD protein aggregates in the brain composed of the amyloid-β-peptide (Aβ), which is called amyloid plaques.

The amyloid-β-peptide is generated by the subsequent degradation of the amyloid precursor protein (APP), a type I transmembrane protein, by two aspartyl proteases, the β-secretase and the γ-secretase. The γ-secretase is a promising target for therapeutic intervention as it liberates various Aβ-peptides with a length of 38, 40, or 42 amino acids. The toxicity depends on the length:Aβ42 is the most toxic species while Aβ38 is regarded to be nontoxic as increased production of Aβ38 does not diminish cellular viability. Several γ-secretase inhibitors (GSI), which decrease total Aβ levels, are developed.

Example- casein kinase 1e (CK1e) inhibitor.


APP processing pathways

2.1.4. γ-secretase modulators18-
Unfortunately, GSIs also inhibit cleavage of other secretase substrates, including Notch. It is this inhibition of Notch processing which is responsible for adverse events in clinical trials, particularly gastrointestinal and immunological toxicities.In contrast to GSIs, compounds known as γ-secretase modulators (GSMs) inhibit Aβ42 production without interfering in the processing of Notch and other substrates.

They are thought to intervene at an allosteric site on γ-secretase and shift the APP cleavage site so that shorter, soluble, non-toxic peptides (e.g., Aβ38) are produced instead of the highly insoluble and neurotoxic Aβ42.

Derivatives of COX inhibitors functioned as modulators of γ-secretase independent of their COX activity. However, Flurizan is a weak GSM that failed in clinical trials testing its ability to treat Alzheimer’s disease.

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