Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.

Reid PR, Bridges TM, Sheffler DJ, Cho HP, Lewis LM, Days E, Daniels JS, Jones CK, Niswender CM, Weaver CD, Conn PJ, Lindsley CW, Wood MR
Bioorg Med Chem Lett. 2011 21 (9): 2697-701

PMID: 21194936 · PMCID: PMC3082000 · DOI:10.1016/j.bmcl.2010.12.015

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.

Copyright © 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (11)

Allosteric Regulation Brain Cells, Cultured Drug Discovery Indoles Inhibitory Concentration 50 Molecular Probes Molecular Structure Receptor, Muscarinic M1 Structure-Activity Relationship Sulfones

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