Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu                         4                         )

Sean R. Bollinger; Darren W. Engers; Joseph D. Panarese; Mary West; Julie L. Engers; Matthew T. Loch; Alice L. Rodriguez; Anna L. Blobaum; Carrie K. Jones; Analisa Thompson Gray; P. Jeffrey Conn; Craig W. Lindsley; Colleen M. Niswender; Corey R. Hopkins

doi:10.1021/acs.jmedchem.8b00994

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ )

Sean R. Bollinger, Darren W. Engers, Joseph D. Panarese, Mary West, Julie L. Engers, Matthew T. Loch, Alice L. Rodriguez, Anna L. Blobaum, Carrie K. Jones, Analisa Thompson Gray, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R. Hopkins

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

23 Scopus citations

Abstract

This work describes the discovery and characterization of novel 6-(1H-pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazole-3-carboxamides as mGlu ₄ PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu ₄ PAMs. From this work, 27o (VU6001376) was identified as a potent (EC ₅₀ = 50.1 nM, 50.5% GluMax) and selective mGlu ₄ PAM with an excellent rat DMPK profile (in vivo rat CL _p = 3.1 mL/min/kg, t _1/2 = 445 min, CYP1A2 IC ₅₀ > 30 μM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.

Original language	English (US)
Pages (from-to)	342-358
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00994
State	Published - Oct 1 2019
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.8b00994

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Bollinger, S. R., Engers, D. W., Panarese, J. D., West, M., Engers, J. L., Loch, M. T., Rodriguez, A. L., Blobaum, A. L., Jones, C. K., Thompson Gray, A., Conn, P. J., Lindsley, C. W., Niswender, C. M., & Hopkins, C. R. (2019). Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) Journal of Medicinal Chemistry, 62(1), 342-358. https://doi.org/10.1021/acs.jmedchem.8b00994

Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) . / Bollinger, Sean R.; Engers, Darren W.; Panarese, Joseph D. et al.
In: Journal of Medicinal Chemistry, Vol. 62, No. 1, 01.10.2019, p. 342-358.

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

Bollinger, SR, Engers, DW, Panarese, JD, West, M, Engers, JL, Loch, MT, Rodriguez, AL, Blobaum, AL, Jones, CK, Thompson Gray, A, Conn, PJ, Lindsley, CW, Niswender, CM & Hopkins, CR 2019, ' Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) ', Journal of Medicinal Chemistry, vol. 62, no. 1, pp. 342-358. https://doi.org/10.1021/acs.jmedchem.8b00994

Bollinger SR, Engers DW, Panarese JD, West M, Engers JL, Loch MT et al. Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) Journal of Medicinal Chemistry. 2019 Oct 1;62(1):342-358. doi: 10.1021/acs.jmedchem.8b00994

Bollinger, Sean R. ; Engers, Darren W. ; Panarese, Joseph D. et al. / Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu ₄ ) In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 1. pp. 342-358.

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