Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs

Abstract This letter describes the chemical optimization of a novel series of M 4 positive allosteric modulators(PAMs) based on a 5-amino-thieno[2,3- c ] pyridazinecore, developed via iterative parallel synthesis, and culminatingin the highly utilized rodent in vivo tool compound, VU0467154 ( 5 ). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulatorprograms (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).