Optimization of M 4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology

Abstract This letter describes the further chemical optimization of the 5-amino-thieno[2,3- c ]pyridazine series (VU0467154/VU0467485) of M 4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 ( 8p ). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p , this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.