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

Authors

Engers JL Julie L , Bollinger KA Katrina A , Capstick RA Rory A , Long MF Madeline F , Bender AM Aaron M , Dickerson JW Jonathan W , Peng W Weimin , Presley CC Christopher C , Cho HP Hyekyung P , Rodriguez AL Alice L , Niswender CM Colleen M , Moran SP Sean P , Xiang Z Zixiu , Blobaum AL Anna L , Boutaud O Olivier , Rook JM Jerri M , Engers DW Darren W , Conn PJ P Jeffrey , Lindsley CW Craig W .
ACS chemical neuroscience. 2024 08 28; 15(18).
3421-3433

PMID: 39197083

Abstract

Herein we report progress toward a backup clinical candidate to the M positive allosteric modulator (PAM) VU319/ACP-319. Scaffold-hopping from the pyrrolo[2,3-]pyridine-based M PAM VU6007477 to isomeric pyrrolo[3,2-]pyridine and thieno[3,2-]pyridine congeners identified several backup contenders. Ultimately, VU6007496, a pyrrolo[3,2-]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 screen, preventing further development. However, VU6007496 proved to be a highly selective and CNS penetrant M 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 tool compound in rats and nonhuman primates, but not mouse, to study selective M activation.