Alzheimer’s disease (AD) is the most prevalent form of dementia in the aged population characterized by the presence of senile plaques and neurofibrillary tangles associated to astrogliosis and inflammation. So far, there is no way to halt or slow-down AD and available treatments are only symptomatic. There is thus a constant need of developing novel therapeutic strategies. Several lines of evidence indicate that the blockade of the A2A receptor constitutes promising approaches for AD. But our poor knowledge of the overall effect of A2AR blockade in AD models and the difficulty to conceive antagonists able to reach clinical stage limit the development of A2AR-based clinical trials. In this project, we aim to develop several original families of compounds with satisfactory DMPK properties and to evaluate the effect of chronic and specific A2AR blockade in AD transgenic models mimicking amyloid side. This represents a major step to the clinical valorization of A2AR antagonists in AD.
Identification of original chemical A2AR antagonists is based on recently published crystalline structures. 1,2 A first family “Tic-guanidine” was first identified as promising and docking studies showed that these compounds share a similar binding mode as the reference ligand ZM-2413851 in the A2aR binding site.
In silico docking study of original compounds and of the national chemical library then enabled us to identify promising privileged structures that could be easily pharmacomodulated using original chemical pathways. 5 families are currently under development and their affinity, functionality and selectivity are being evaluated.3 DMPK properties will then be evaluated on the most relevant compounds.
compounds with satisfactory DMPK properties and to evaluate the effect of chronic and specific A2AR blockade in AD transgenic models mimicking amyloid side. This represents a major step to the clinical valorization of A2AR antagonists in AD.
1. Jaakola et al. Science 2008, 322, 1211.
2. Congreve et al. J Med Chem. 2012, 55, 898.
3. Moas Heloire et al. Eur J Med Chem. 2015, 106, 15.