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

Andrew S. Felts; Alice L. Rodriguez; Ryan D. Morrison; Anna L. Blobaum; Frank W. Byers; J. Scott Daniels; Colleen M. Niswender; P. Jeffrey Conn; Craig W. Lindsley; Kyle A. Emmitte

doi:10.1016/j.bmcl.2018.04.053

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

Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Anna L. Blobaum, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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Abstract

Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu₅ negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu₅ 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 mGlu₅ 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.

Original language	English
Pages (from-to)	1679-1685
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2018.04.053
State	Published - 1 Jun 2018

Keywords

Central nervous system (CNS)
G protein-coupled receptor (GPCR)
Metabotropic glutamate receptor subtype 5 (mGlu)
Negative allosteric modulator (NAM)
Quinoline

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Felts, A. S., Rodriguez, A. L., Morrison, R. D., Blobaum, A. L., Byers, F. W., Daniels, J. S., Niswender, C. M., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2018). Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorganic and Medicinal Chemistry Letters, 28(10), 1679-1685. https://doi.org/10.1016/j.bmcl.2018.04.053

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title = "Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5",

abstract = "Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 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 mGlu5 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.",

keywords = "Central nervous system (CNS), G protein-coupled receptor (GPCR), Metabotropic glutamate receptor subtype 5 (mGlu), Negative allosteric modulator (NAM), Quinoline",

author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Blobaum, {Anna L.} and Byers, {Frank W.} and Daniels, {J. Scott} and Niswender, {Colleen M.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle A.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

year = "2018",

month = jun,

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doi = "10.1016/j.bmcl.2018.04.053",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Felts, AS, Rodriguez, AL, Morrison, RD, Blobaum, AL, Byers, FW, Daniels, JS, Niswender, CM, Conn, PJ, Lindsley, CW & Emmitte, KA 2018, 'Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 10, pp. 1679-1685. https://doi.org/10.1016/j.bmcl.2018.04.053

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AU - Felts, Andrew S.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Blobaum, Anna L.

AU - Byers, Frank W.

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle A.

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AB - Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 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 mGlu5 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.

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KW - G protein-coupled receptor (GPCR)

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

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Keywords

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