Disseny i síntesi de nous compostos multipotents per al tractament de la malaltia d’Alzheimer

Abstract

El principal factor desencadenant de la neurodegeneració que caracteritza la malaltia d’Alzheimer (MA) és el pèptid β-amiloide (Aβ). La formació incrementada d’aquest pèptid i la seva agregació es troben a l’inici d’una cascada de processos neurotòxics que culminen amb una disfunció neuronal generalitzada i mort neuronal. Actualment, es troben en fase clínica diferents candidats a fàrmacs anti-Alzheimer denominats “modificadors de la malaltia” que van dirigits a inhibir la formació o l’agregació de l’Aβ. S’espera que aquests compostos puguin prevenir o frenar la neurodegeneració de la MA.

L’arsenal terapèutic actual per al tractament de la MA continua estant dominat per un grup de fàrmacs que van estar desenvolupats per a tractar la seva simptomatologia, la qual apareix com a conseqüència de dèficits de diferents neurotransmissors, especialment d’acetilcolina (ACh), al sistema nerviós central. Concretament, quatre dels cinc fàrmacs actualment comercialitzats per al tractament de la MA són un grup d’inhibidors de l’enzim acetilcolinesterasa (AChE), enzim responsable de la hidròlisi de l’ACh.

Recentment s’ha demostrat que l’AChE es pot unir a l’Aβ accelerant la seva agregació, augmentant-ne la neurotoxicitat i promovent el deteriorament cognitiu. A través del denominat lloc perifèric, el qual es troba a l’entrada d’una gorja catalítica d’uns 20 Å de longitud, al fons de la qual es troba el lloc catalític de l’enzim. Així, el bloqueig simultani amb ambdós llocs d’unió (actiu i perifèric) ha portat al desenvolupament dels denominats inhibidors d’AChE de lloc d’unió dual, els quals són candidats molt prometedors a fàrmacs anti-Alzheimer amb potencial per modificar positivament el curs de la malaltia.

D’altra banda, degut al caràcter multifactorial de l’etiologia de la MA s’està començant a considerar el desenvolupament de nous compostos multipotents capaços d’interaccionar amb diferents dianes biològiques involucrades en la malaltia com a única via per a aconseguir incidir eficientment sobre la malaltia, com ara, l’estrès oxidatiu degut a la sobreproducció d’espècies reactives d’oxigen (ROS). S’ha demostrat que els compostos quelants d’ions metàl•lics són capaços d’inhibir la producció de ROS i s’està considerant la utilització d’antioxidants naturals contra processos en els quals està implicat l’estrès oxidatiu, com és el cas de la MA.

The main factor triggering the process of neurodegeneration characteristic of Alzheimer's disease (AD) is the so-called β-amyloid peptide (Aβ). The increased formation of this peptide and its aggregation are placed at the beginning of a cascade of neurotoxic processes culminating in widespread neuronal dysfunction and death. Currently, there are several "disease-modifying" anti-Alzheimer drug candidates in clinical trials aimed at inhibiting the formation or aggregation of Aβ. It is expected that these compounds can prevent or slow the neurodegeneration of AD.

The current treatment available for the treatment of AD is still dominated by a group of drugs that were developed to treat its symptoms, which appear as a result of the decrease in the production of various neurotransmitters, particularly acetylcholine (ACh) at the central nervous system. Consequently, the use of cholinomimetic agents capable to compensate this deficit should reduce cholinergic symptoms of AD. In fact, four out of the five drugs currently marketed for the treatment of AD are a group of inhibitors of the enzyme acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of ACh at the synapses, which increase levels of the neurotransmitter, thus reducing the symptoms of AD.

Recently, it has been demonstrated that the enzyme AChE can bind to Aβ accelerating its aggregation, increasing the neurotoxicity and promoting cognitive decline. The binding site of AChE to Aβ is the so-called peripheral site, which is located at the entrance of a catalytic gorge of about 20 Å length, at the bottom of which the catalytic site of the enzyme is placed, where the hydrolysis of ACh takes place. Thus, the blockade of the peripheral site of AChE should lead to an inhibition of Aβ aggregation and of the neurodegenerative cascade. In addition, the particular architecture of the enzyme where the active and peripheral sites are separated but close enough to allow a molecule to simultaneously interact with the two binding sites has led to the development of dual binding site AChE inhibitors, which are very promising anti-Alzheimer drug candidates expected to positively alter the course of disease.

Moreover, due to the multifactorial nature of the etiology of AD, development of multipotent compounds capable of interacting with different biological targets involved in the disease is beginning to be considered as the only way to achieve efficient impact on the course of the disease. Aβ aggregation plays a crucial role in the pathogenesis of AD, inducing processes in the neurodegenerative cascade and oxidative stress due to overproduction of reactive oxygen species (ROS). It also appears that the Cu2+ and Fe3+ ions are capable of generating ROS, after binding to the Aβ For these reasons, the metal ions and oxidative stress are interesting targets to modulate by multipotent anti-Alzheimer drug candidates. Thus, it has been shown that the compounds capable of chelating metal ions are able to inhibit the production of ROS and the use of natural antioxidants is also being considered to block the oxidative stress involved in Aβ. The aim of the present PhD is to develop multipotent compounds capable to interact with different biological targets involved in AD, namely cholinesterases, Aβ and oxidative stress, in order to block its neurodegenerative cascade.