Conceptual Framework of the Design of Pleiotropic Drugs against Alzheimer's Disease

Abstract

The multifactorial nature of some diseases, particularly neurodegenerative diseases such as Alzheimer's disease, frequently requires the use of several drugs. These drug cocktails are not without drawbacks in terms of increased adverse effects, drug-drug interactions or low adherence to treatment. The use of pleiotropic drugs, which combine, within a single molecule, several activities directed against distinct therapeutic targets, makes it possible to overcome some of these problems. In addition, these pleiotropic drugs generally lead to the expression of a synergy of effects, sometimes greater than that observed with a combination of drugs. This article will review, through recent examples, the different kinds of pleiotropic drugs being studied or already present on the market of medicines, with a focus on the structural aspect of such drug design.

Keywords: Alzheimer’s disease; drug; neurodegeneration; pleiotropic.

Figure 1

Differences between ordinary (A) and pleiotropic (B) active ingredients.

Figure 2

Different categories of pleiotropic compounds.

Figure 3

Structures of different conjugates with an immolable chemical bond.

Figure 4

Donepezil interacts with the catalytic and peripheral anionic sites of AChE. PDB code: 1EVE. The compound and the side chains of the binding site residues are represented by the stick-like shapes. This figure was made with PYMOL (DeLano Scientific, 2002, San Carlos, CA, USA).

Figure 5

Structure of Memagal and chloro-tacrine/tryptophan non-dissociable conjugates.

Figure 6

Prodrugs of pleiotropic agents.

Figure 7

Structure of donecopride, propargylaminodonepezil and indolic analogue of donecopride.

Figure 8

Structure of conformationally constrained donecopride analogue in phenylpyrazole series and contilisant.

Figure 9

Structure of curcumin and synthetic analogues with pleiotropic activities.

Figure 10

Structure of Anavex 2-73.