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

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

  • Bioorg Med Chem Lett. 2011 May 1;21(9):2697-701. doi: 10.1016/j.bmcl.2010.12.015.
Paul R Reid 1,  Thomas M Bridges,  Douglas J Sheffler,  Hyekyung P Cho,  L Michelle Lewis,  Emily Days,  J Scott Daniels,  Carrie K Jones,  Colleen M Niswender,  C David Weaver,  P Jeffrey Conn,  Craig W Lindsley,  Michael R Wood
Affiliations

Affiliation

  • 1 Vanderbilt Institute of Chemical Biology/Chemical Synthesis Core, Nashville, TN 37232, USA.
PMID: 21194936 DOI: 10.1016/j.bmcl.2010.12.015
Abstract

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.

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