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Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe |
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| Authors: | Reid Paul R Bridges Thomas M Sheffler Douglas J Cho Hyekyung P Lewis L Michelle Days Emily Daniels J Scott Jones Carrie K Niswender Colleen M Weaver C David Conn P Jeffrey Lindsley Craig W Wood Michael R |
| Institution: | a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA b Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA c Vanderbilt Program in Drug Discovery, Nashville, TN 37232, USA d Vanderbilt Specialized Chemistry Center(MLPCN), Nashville, TN 37232, USA e Vanderbilt Institute of Chemical Biology/Chemical Synthesis Core, Nashville, TN 37232, USA f U.S. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA |
| Abstract: | This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 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 M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio. |
| Keywords: | Muscarinic Acetylcholine Positive allosteric modulator (PAM) ML169 BQCA Alzheimer&rsquo s disease MLPCN |
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