Developing a Better Benzoxazine Drug for Treating Alzheimer's Disease Through Lead Optimization of Etifoxine

Xiaofan Liu, PhD
Department of Neurology
Division of Basic Neuroscience Research
Poster Overview

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly with a population of 50 million people worldwide. To date, there are very few FDA approved drugs and they cannot directly prevent AD, but simply treat mild cognitive symptoms. We are interested in developing potent and safe small molecule drugs for AD by targeting protein receptors in central nervous system using etifoxine a known anxiolytic drug which was previously approved in Europe as a lead compound for optimization. In addition to its anxiolytic properties in human, recent pre-clinical studies have shown beneficial effects of Etifoxine in a number of neurodegenerative disease models. It has been found that etifoxine indirectly modulates the targeting protein receptor via stimulation of protective neurosteroid. A library of drug molecules is synthesized based on the chemical structure of etifoxine and is being screened for activity. The potency of the compounds is evaluated by neuronal cell assay to see is there is high drug-protein binding affinity and increased level of helpful neurosteroid. Preliminary data shows a few synthesized analogs have promising activity and good pharmacokinetic.

Scientific Abstract

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly with a population of 50 million people worldwide. To date, there are very few FDA approved drugs and they cannot directly prevent AD, but simply treat mild cognitive symptoms. We are interested in developing potent and safe small molecule drugs for AD by targeting both neurotransmitter gamma- aminobutyric acid receptor (GABAa) and translocator protein (TSPO) receptor using etifoxine a GABAa ligand as a lead compound for optimization. TSPO ligands have shown neuroprotective effects in studies, however the oral administration can be tough because most current ligands have poor water solubility. Since it has been found that etifoxine also potently binds to TSPO and indirectly modulates GABAA receptor via stimulation of protective neurosteroid (eg. pregnenolone) production, an alternative approach to the administration of neurosteroids is the indirect promotion of local steroid production within the central nervous system. A library of etifoxine analogs is chemically synthesized for structure activity relationship study. The potency of the compounds is evaluated by LPS (Lipopolysaccharide) inflammation assay and investigating pregnenolone level with ELISA (Enzyme-linked Immunosorbent Assay) in microglial cell. Preliminary data shows stereo-pure desethyl-etifoxine and trifluoromethyl pyridoxazine analogs have promising activity and good pharmacokinetic.

Clinical Implications
Currently the project is in lead optimization stage which involves pharmacokinetics studies on mice models. The best drug candidate will be carried forward to preclinical study.
Research Areas
Authors
Xiaofan Liu, Michael Cleary, Andrew Buglass, Luu Pham, Kevin Hodgetts
Principal Investigator
Kevin Hodgetts

Explore Other Posters

Leave a Reply

Your email address will not be published. Required fields are marked *