Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.

Panarese JD, Cho HP, Adams JJ, Nance KD, Garcia-Barrantes PM, Chang S, Morrison RD, Blobaum AL, Niswender CM, Stauffer SR, Conn PJ, Lindsley CW
Bioorg Med Chem Lett. 2016 26 (15): 3822-5

PMID: 27173801 · PMCID: PMC5082649 · DOI:10.1016/j.bmcl.2016.04.083

This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.

Copyright © 2016 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Allosteric Regulation Animals Central Nervous System Central Nervous System Agents Dose-Response Relationship, Drug Drug Discovery Heterocyclic Compounds Molecular Structure Pyridines Pyrroles Rats Receptor, Muscarinic M1 Structure-Activity Relationship

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