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.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Brain / drug effects*
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Cells, Cultured
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Drug Discovery*
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology*
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Inhibitory Concentration 50
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Molecular Probes / chemical synthesis*
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Molecular Probes / chemistry
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Molecular Probes / pharmacology*
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Molecular Structure
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Receptor, Muscarinic M1 / metabolism*
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology*
Substances
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Indoles
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Molecular Probes
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Receptor, Muscarinic M1
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Sulfones
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VU 0405652