Up to 80% of individuals with Parkinson’s develop Parkinson’s disease dementia (PDD), which is characterized by a progressive loss of memory and a decline in cognitive function. Available drugs approved to treat PDD can lessen the extent of cognitive decline caused by loss of activity in cholinergic brain circuits (chemical messenger system) to a limited degree. However, these drugs have considerable side effects. We aim to design novel molecules that are positive allosteric modulators of the M1 muscarinic acetylcholine receptor (M1 mAchR), thereby targeting the same brain circuits with fewer side effects.
We believe that small molecules that affect the function of the M1 mAChR in a highly selective manner have the potential to deliver novel, well-tolerated and efficacious drugs to treat learning and memory deficits in individuals with PDD.
We have generated small molecules of novel chemical classes that are positive allosteric modulators of the M1 mAChR and have a good understanding of the structure-activity relationship of these molecules. Based on this knowledge, we will synthesize these molecules and optimize them for target engagement in the brain and safety.
Impact on Diagnosis/Treatment of Parkinson’s disease:
We believe that our M1 mAChR PAM program has the potential to bring the first treatment for PDD of this new drug class to patients. Given the high unmet need of individuals with PDD, we think that development of a symptomatic treatment will bring significant benefit to individuals with Parkinson's disease and their caregivers.
Next Steps for Development:
The next steps after completion of this study will include further optimization toward clinical candidate molecules, including the demonstration of efficacy in pre-clinical cognition models. Clinical candidate molecules will then move through regulatory phases of development, starting with pre-clinical safety pharmacology and toxicology studies, followed by human clinical trials.
Our study aimed to identify novel small-molecule compounds that affect the function of the M1 muscarinic acetylcholine receptor (M1 mAChR) -- an assembly of proteins on the surface of the nerve cell -- but have no effect on other receptors. We believe that such compounds could help develop novel, well-tolerated and effective drugs to treat learning and memory disturbances in individuals with Parkinson's disease (PD) dementia.
We started this study with ASN-408, our most promising compound, which is a partially optimized positive allosteric modulator (PAM) of the M1 mAChR (M1 PAM). Positive allosteric modulators, including ASN-408, enhance the receptor's function. We then created new compounds with much better properties compared with ASN-408, the best of which demonstrated excellent activity in pre-clinical modes. We will continue to optimize this new compound and test it in pre-clinical models with learning and memory disturbances.
The identification of novel M1 PAMs with improved properties in this project was a key step toward the identification of compounds to be used in clinical trials. These compounds will then have to pass all the stages of drug development, starting with pre-clinical safety studies and followed by clinical trials.