Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain

Stephanie Brumfield; Peter Korakas; Lisa S. Silverman; Deen Tulshian; Julius J. Matasi; Li Qiang; Chad E. Bennett; Duane A. Burnett; William J. Greenlee; Chad E. Knutson; Wen Lian Wu; T. K. Sasikumar; Martin Domalski; Rosalia Bertorelli; Mariagrazia Grilli; Gianluca Lozza; Angelo Reggiani; Cheng Li

doi:10.1016/j.bmcl.2012.09.048

Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain

Stephanie Brumfield
, Peter Korakas
, Lisa S. Silverman
, Deen Tulshian
, Julius J. Matasi
, Li Qiang
, Chad E. Bennett
, Duane A. Burnett
, William J. Greenlee
, Chad E. Knutson
, Wen Lian Wu
, T. K. Sasikumar
, Martin Domalski
, Rosalia Bertorelli
, Mariagrazia Grilli
, Gianluca Lozza
, Angelo Reggiani
, Cheng Li

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

Abstract

High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

Original language	English
Pages (from-to)	7223-7226
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2012.09.048
Publication status	Published - 1 Dec 2012
Externally published	Yes

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10.1016/j.bmcl.2012.09.048

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Brumfield, S., Korakas, P., Silverman, L. S., Tulshian, D., Matasi, J. J., Qiang, L., Bennett, C. E., Burnett, D. A., Greenlee, W. J., Knutson, C. E., Wu, W. L., Sasikumar, T. K., Domalski, M., Bertorelli, R., Grilli, M., Lozza, G., Reggiani, A., & Li, C. (2012). Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain. Bioorganic and Medicinal Chemistry Letters, 22(23), 7223-7226. https://doi.org/10.1016/j.bmcl.2012.09.048

@article{1587d75456634399a1ef1abc6ed105db,

title = "Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain",

abstract = "High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.",

author = "Stephanie Brumfield and Peter Korakas and Silverman, \{Lisa S.\} and Deen Tulshian and Matasi, \{Julius J.\} and Li Qiang and Bennett, \{Chad E.\} and Burnett, \{Duane A.\} and Greenlee, \{William J.\} and Knutson, \{Chad E.\} and Wu, \{Wen Lian\} and Sasikumar, \{T. K.\} and Martin Domalski and Rosalia Bertorelli and Mariagrazia Grilli and Gianluca Lozza and Angelo Reggiani and Cheng Li",

year = "2012",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2012.09.048",

language = "English",

volume = "22",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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}

Brumfield, S, Korakas, P, Silverman, LS, Tulshian, D, Matasi, JJ, Qiang, L, Bennett, CE, Burnett, DA, Greenlee, WJ, Knutson, CE, Wu, WL, Sasikumar, TK, Domalski, M, Bertorelli, R, Grilli, M, Lozza, G, Reggiani, A & Li, C 2012, 'Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 23, pp. 7223-7226. https://doi.org/10.1016/j.bmcl.2012.09.048

TY - JOUR

T1 - Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain

AU - Brumfield, Stephanie

AU - Korakas, Peter

AU - Silverman, Lisa S.

AU - Tulshian, Deen

AU - Matasi, Julius J.

AU - Qiang, Li

AU - Bennett, Chad E.

AU - Burnett, Duane A.

AU - Greenlee, William J.

AU - Knutson, Chad E.

AU - Wu, Wen Lian

AU - Sasikumar, T. K.

AU - Domalski, Martin

AU - Bertorelli, Rosalia

AU - Grilli, Mariagrazia

AU - Lozza, Gianluca

AU - Reggiani, Angelo

AU - Li, Cheng

PY - 2012/12/1

Y1 - 2012/12/1

N2 - High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

AB - High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1 = 10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.

UR - https://www.scopus.com/pages/publications/84869081295

U2 - 10.1016/j.bmcl.2012.09.048

DO - 10.1016/j.bmcl.2012.09.048

M3 - Article

SN - 0960-894X

VL - 22

SP - 7223

EP - 7226

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain

Abstract

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