Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.

Felts AS, Rodriguez AL, Morrison RD, Blobaum AL, Byers FW, Daniels JS, Niswender CM, Conn PJ, Lindsley CW, Emmitte KA
Bioorg Med Chem Lett. 2018 28 (10): 1679-1685

PMID: 29705142 · PMCID: PMC6142812 · DOI:10.1016/j.bmcl.2018.04.053

Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Allosteric Regulation Animals Dose-Response Relationship, Drug Drug Discovery Humans Male Molecular Structure Pyrimidines Quinolines Rats Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship

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