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

ABSTRACT: 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

SUBMITTER: Engers JL 

PROVIDER: S-EPMC11413853 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature