The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors

Christina A. Gates; Donald S. Backos; Philip Reigan; Nicholas R. Natale

doi:10.3390/molecules28196800

The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors

Christina A. Gates, Donald S. Backos, Philip Reigan, Nicholas R. Natale

Biomedical and Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR_1a, mGluR₅, or mGluR₈. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n.

Original language	English
Article number	6800
Journal	Molecules
Volume	28
Issue number	19
DOIs	https://doi.org/10.3390/molecules28196800
State	Published - Sep 25 2023

Funding

This research was funded by the ALSAM Foundation via grants to N.R.N., D.S.B., and P.R. In addition, N.R.N. thanks the University of Montana for Small Grants MRA796 and 325490, and C.A.G. acknowledges the support of the ASUM Research and Creative Scholarship and the Besancon Scholarship.

Funder number
325490, MRA796

Keywords

isoxazole
lateral metalation
metabotropic glutamate receptor
Isoxazoles/pharmacology
Models, Chemical
Allosteric Regulation
Benzamides
Molecular Dynamics Simulation

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title = "The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors",

abstract = "Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM\&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n.",

keywords = "isoxazole, lateral metalation, metabotropic glutamate receptor, Isoxazoles/pharmacology, Models, Chemical, Allosteric Regulation, Benzamides, Molecular Dynamics Simulation",

author = "Gates, \{Christina A.\} and Backos, \{Donald S.\} and Philip Reigan and Natale, \{Nicholas R.\}",

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AU - Gates, Christina A.

AU - Backos, Donald S.

AU - Reigan, Philip

AU - Natale, Nicholas R.

PY - 2023/9/25

Y1 - 2023/9/25

N2 - Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n.

AB - Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated. One uses the fully formed [3,4-d] with an N6-aryl with and without halogens. These underwent successful selective lateral metalation and electrophilic quenching (LM&EQ) at the C3 of the isoxazole. In a second set of analogs, a phenyl group was introduced at the C4 position of the [3,4-d] ring via a condensation of 4-phenylacetyl-3-ethoxcarbonyl-5-methyl isoxazole with the corresponding hydrazine to generate the 3,4-ds 2b and 2j to 2n.

KW - isoxazole

KW - lateral metalation

KW - metabotropic glutamate receptor

KW - Isoxazoles/pharmacology

KW - Models, Chemical

KW - Allosteric Regulation

KW - Benzamides

KW - Molecular Dynamics Simulation

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DO - 10.3390/molecules28196800

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SN - 1420-3049

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JO - Molecules

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ER -

The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors

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