Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1.

Manka JT, Rodriguez AL, Morrison RD, Venable DF, Cho HP, Blobaum AL, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Emmitte KA
Bioorg Med Chem Lett. 2013 23 (18): 5091-6

PMID: 23932792 · PMCID: PMC3901432 · DOI:10.1016/j.bmcl.2013.07.029

Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Allosteric Regulation Animals Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System Dose-Response Relationship, Drug Enzyme Inhibitors Humans Molecular Structure Pyrroles Rats Receptors, Metabotropic Glutamate Structure-Activity Relationship

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