M4 muscarinic acetylcholine receptor (mAChR4) activators offer a novel strategy for the treatment of psychosis in a number of neurological disorders. Advancement of non-selective orthosteric muscarinic agonists has traditionally been challenging due to poor toleration and side effects traditionally linked to concomitant activation of other mAChR subtypes (M1- M3). To overcome the issue of subtype selectivity, we focused on developing brain penetrant M4 selective positive allosteric modulators (PAMs). This presentation will focus on the design efforts employed to overcome a number of specific challenges in the discovery of novel M4 PAM series, ultimately resulting in the identification of high quality compounds that were suitable for development. Strategies to overcome brain penetration challenges will be also be presented.<br/>

Optimization and identification of brain penetrant, M4 subtype-selective muscarinic receptor positive allosteric modulator (M4 PAM) clinical candidate

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.