Discovery of VU6007496: Challenges in the Development of an M1 Positive Allosteric Modulator Backup Candidate

Herein we report progress toward a backup clinical candidate to the M1 positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo­[2,3-b]­pyridine-based M1 PAM VU6007477 to isomeric pyrrolo­[3,2-b]­pyridine and thieno­[3,2-b]­pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo­[3,2-b]­pyridine, advanced into late stage profiling, only to be plagued with unanticipated, species-specific metabolism and active/toxic metabolites which were identified in our phenotypic seizure liability in vivo screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M1 PAM, with minimal agonism, that displayed excellent multispecies IV/PO pharmacokinetics (PK), CNS penetration, no induction of long-term depression (or cholinergic toxicity) and robust efficacy in novel object recognition (minimum effective dose = 3 mg/kg p.o.). Thus, VU6007496 can serve as another valuable in vivo tool compound in rats and nonhuman primates, but not mouse, to study selective M1 activation.