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
  • 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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