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Current AChE inhibitors expose side effects

Although the origin of Alzheimer's disease (AD) is still under debate, amyloid plaques and neurofibrillary tangles observed in postmortem brain studies in neurocortex and hippocampus regions are held responsible for the devastating clinical effects of the disease. Another important and significant aspect of neurodegeneration in the brain of AD patients is the loss of the basal forebrain cholinergic system, thought to play a crucial role in producing cognitive impairments and memory deficiency.


Therefore, enhancement of the central cholinergic transmission has been considered as a promising approach for the symptomatic treatment of AD. Among the diverse strategies explored acetylcholinesterase (AChE) inhibitors have been extensively studied.
This approach has provided Acetylcholine esterase inhibitors is the current treatment for Alzheimer's disease the sole clinically effective method for a palliative treatment of mild to moderate AD.


Over the past decade, several AChE inhibitors have been launched on the market. Although all AChE inhibitors employed in AD therapy exhibit a preferential action in the central nervous system (CNS), the manifestation of peripheral activity in the course of the treatment causes serious adverse effects on peripheral organs and seriously limits the therapeutic potential of these cholinesterase inhibitors.
Therefore, the design of central selective AChE inhibitors free from adverse peripheral effects remains a major challenging therapeutic goal.


Current AChE inhibitors mechanisms of action :
not only restoring the choloinergic balance in the brain

VFP Therapies target symptomatic treatment of Alzheimer's disease

VFP Therapies introduced a “biooxidisable prodrug” which, after having crossed the blood-brain barrier (BBB), is expected to be converted to the parent drug in the CNS, via a redox-activation process.


VFP Therapies aim is to report herein the design, synthesis and preliminary in vitro and on animal's biological evaluation of these new potential central selective AChE inhibitors.


 “Bio-oxidisable prodrug” design of cyclic drug analogues

The design of this “bio-oxidisable prodrug” approach is closely connected with the action mechanism of AChE inhibitors. Whereas some current drugs are competitive inhibitors, another displays a pseudo irreversible inhibition involving the carbamylation of the serine hydroxyl group located at the “esterasic site” of the enzyme. Both classes of these inhibitors share in common a tertiary amine which is known to play a central role in the mechanism of AChE inhibition.


At physiological pH, charge which binds to the “catalytic anionic site” of the enzyme. This binding element, although not sufficient, is essential in the design of these inhibitors. It is also conceptually important to note that while the charged bioactive form cannot cross the BBB by passive diffusion, both central and peripheral cholinergic activities commonly observed with these inhibitors stem from the existence of an acid–base equilibrium by permitting the neutral inactive form to cross this physiological barrier.


On the basis of these mechanistic considerations, a prodrug approach was envisaged to design central selective AChE inhibitors by temporarily masking the positive charge at the periphery. To reach this goal, VFP Therapies focused its attention on cyclic rivastigmine analogues 1 as appealing prodrug candidates.


Although 1,4-dihydroquinoline carbamates 1 are structurally closely related to rivastigmine, these analogues mainly differ in that they possess a non-protonable enamine nitrogen atom at physiological pH and consequently cannot bind to the “anionic site” of the enzyme.


After gaining access to the brain through the BBB by passive diffusion, oxidation of the 1,4-dihydroquinoline 1 would generate the corresponding quaternary quinolinium salt 2, allowing the latter to interact with the “anionic site” by unmasking the positive charge.


The resulting permanently charged quinolinium salt 2 can no longer re-cross the BBB, in contrast to most other previously reported AChE inhibitors for which both neutral and charged forms are in equilibrium at physiological pH. This ionic species “locked-in” into the brain is expected to display a central selective AChE inhibitory activity, thus exerting ameliorating effects on cholinergic deficits without showing excessive peripheral effects.


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Download a more generic paper detailing the currently used vectorization strategies.

 VFP Therapies designed a “bio-oxidisable prodrug” 1 for central selective AChE inhibitory activity


This ideal scenario may be compromised if peripheral oxidation of the 1.4-dihydroquinoline 1 takes place. Indeed, redox activation of the prodrug 1 closely related to the conversion of the NAD(P)H->NAD(P) coenzyme system may arise easily everywhere in the body.


This undesired phenomenon could be controlled via the redox stability of the bioprecursor.


The presence of an electron withdrawing group (EWG) at C-3 is essential to the stabilization of the enamine function in prodrug 1.


This stabilizing element may be helpful to find the delicate balance between stabilization of the prodrug 1 at the periphery and its activation in the CNS. Although 1,4-dihydropyridine-type compounds have been widely developed by Bodor and Prokai for targeting neuroactive compounds to the brain, the use of this redox chemical delivery system to design new prodrug strategies has remained almost unexplored.


However, due to its high hydrophilicity, the potential resulting quinolinium salt 2 which might be formed prematurely in the periphery is expected to be easily eliminated from the peripheral circulation by the kidneys and bile.

In vitro selection :
High activity ratio API/Bioprecursor Animal trials :
Bioprecursor Gous 1 compared to a commercial product


A series of new carbamylated quinolinium salts 2, structurally related to cyclic analogues of an existing drug, exhibited high AChE inhibitory activity with IC values in the nanomolar range.


Interestingly, the corresponding reduced forms 1 proved to be inactive in inhibiting AChE. These results pave the way for the development of VFP Therapies novel “bio-oxidisable prodrug” by means of such redox systems with the aim to reduce undesirable peripheral activity reported with marketed AChE inhibitors.


At this stage, the key to success in this “bio-oxidisable prodrug” strategy lies in the preferential redox activation of prodrug 1 in the CNS, versus periphery.


Besides the activity as AChE inhibitors, our hits are currently being screened on other biological receptors such as butyrylcholinesterase, serotonin receptors, kinases...

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