Synthesis and Structure–Activity Relationships of Allosteric Potentiators of the M₄ Muscarinic Acetylcholine Receptor

Abstract

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR data for a novel series of M4 positive allosteric modulators (PAMs). This effort identified key moieties that improved microsomal stability and physiochemical properties. Moreover, this series displayed an order of magnitude greater potency for human versus rat M4, providing compounds with EC50 values in the 100 nM range.