Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu 1

Jason T. Manka; Alice L. Rodriguez; Ryan D. Morrison; Daryl F. Venable; Hyekyung P. Cho; Anna L. Blobaum; J. Scott Daniels; Colleen M. Niswender; P. Jeffrey Conn; Craig W. Lindsley; Kyle A. Emmitte

doi:10.1016/j.bmcl.2013.07.029

Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu ₁

Jason T. Manka, Alice L. Rodriguez, Ryan D. Morrison, Daryl F. Venable, Hyekyung P. Cho, Anna L. Blobaum, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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Abstract

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.

Original language	English
Pages (from-to)	5091-5096
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2013.07.029
State	Published - 15 Sep 2013

Keywords

Allosteric modulator
CNS
GPCR mGlu
Glutamate
Octahydropyrrolo[3,4-c]pyrrole

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10.1016/j.bmcl.2013.07.029

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title = "Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu 1",

abstract = "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.",

keywords = "Allosteric modulator, CNS, GPCR mGlu, Glutamate, Octahydropyrrolo[3,4-c]pyrrole",

author = "Manka, {Jason T.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Venable, {Daryl F.} and Cho, {Hyekyung P.} and Blobaum, {Anna L.} and Daniels, {J. Scott} and Niswender, {Colleen M.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle A.}",

year = "2013",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2013.07.029",

language = "English",

volume = "23",

pages = "5091--5096",

journal = "Bioorganic and Medicinal Chemistry Letters",

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AU - Manka, Jason T.

AU - Rodriguez, Alice L.

AU - Morrison, Ryan D.

AU - Venable, Daryl F.

AU - Cho, Hyekyung P.

AU - Blobaum, Anna L.

AU - Daniels, J. Scott

AU - Niswender, Colleen M.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle A.

PY - 2013/9/15

Y1 - 2013/9/15

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AB - 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.

KW - Allosteric modulator

KW - CNS

KW - GPCR mGlu

KW - Glutamate

KW - Octahydropyrrolo[3,4-c]pyrrole

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JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu ₁

Abstract

Keywords

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