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Title: Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity

Abstract

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. Here, the resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.

Authors:
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+ Show Author Affiliations
  1. Eli Lilly and Company, Indianapolis, IN (United States)
  2. Centro de Investigación Lilly S.A. Avda. de la Industria, Madrid (Spain)
  3. Eli Lilly and Company, San Diego, CA (United States)
  4. Argonne National Lab. (ANL), Argonne, IL (United States)
  5. Eli Lilly and Company, Surrey (United Kingdom)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1340719
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 24; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; antagonists; substituents; selectivity; screening assays; receptors; mGlu2/3 antagonists; LY3020371.HCl; LY341495

Citation Formats

Chappell, Mark D., Li, Renhua, Smith, Stephon C., Dressman, Bruce A., Tromiczak, Eric G., Tripp, Allie E., Blanco, Maria-Jesus, Vetman, Tatiana, Quimby, Steven J., Matt, James, Britton, Thomas C., Fivush, Adam M., Schkeryantz, Jeffrey M., Mayhugh, Daniel, Erickson, Jon A., Bures, Mark G., Jaramillo, Carlos, Carpintero, Mercedes, Diego, José Eugenio de, Barberis, Mario, Garcia-Cerrada, Susana, Soriano, José F., Antonysamy, Stephen, Atwell, Shane, MacEwan, Iain, Condon, Bradley, Sougias, Christine, Wang, Jing, Zhang, Aiping, Conners, Kris, Groshong, Chris, Wasserman, Stephen R., Koss, John W., Witkin, Jeffrey M., Li, Xia, Overshiner, Carl, Wafford, Keith A., Seidel, Wesley, Wang, Xu-Shan, Heinz, Beverly A., Swanson, Steven, Catlow, John T., Bedwell, David W., Monn, James A., Mitch, Charles H., and Ornstein, Paul L. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b01119.
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Chappell, Mark D., Li, Renhua, Smith, Stephon C., Dressman, Bruce A., Tromiczak, Eric G., Tripp, Allie E., Blanco, Maria-Jesus, Vetman, Tatiana, Quimby, Steven J., Matt, James, Britton, Thomas C., Fivush, Adam M., Schkeryantz, Jeffrey M., Mayhugh, Daniel, Erickson, Jon A., Bures, Mark G., Jaramillo, Carlos, Carpintero, Mercedes, Diego, José Eugenio de, Barberis, Mario, Garcia-Cerrada, Susana, Soriano, José F., Antonysamy, Stephen, Atwell, Shane, MacEwan, Iain, Condon, Bradley, Sougias, Christine, Wang, Jing, Zhang, Aiping, Conners, Kris, Groshong, Chris, Wasserman, Stephen R., Koss, John W., Witkin, Jeffrey M., Li, Xia, Overshiner, Carl, Wafford, Keith A., Seidel, Wesley, Wang, Xu-Shan, Heinz, Beverly A., Swanson, Steven, Catlow, John T., Bedwell, David W., Monn, James A., Mitch, Charles H., & Ornstein, Paul L. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity. United States. https://doi.org/10.1021/acs.jmedchem.6b01119
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Chappell, Mark D., Li, Renhua, Smith, Stephon C., Dressman, Bruce A., Tromiczak, Eric G., Tripp, Allie E., Blanco, Maria-Jesus, Vetman, Tatiana, Quimby, Steven J., Matt, James, Britton, Thomas C., Fivush, Adam M., Schkeryantz, Jeffrey M., Mayhugh, Daniel, Erickson, Jon A., Bures, Mark G., Jaramillo, Carlos, Carpintero, Mercedes, Diego, José Eugenio de, Barberis, Mario, Garcia-Cerrada, Susana, Soriano, José F., Antonysamy, Stephen, Atwell, Shane, MacEwan, Iain, Condon, Bradley, Sougias, Christine, Wang, Jing, Zhang, Aiping, Conners, Kris, Groshong, Chris, Wasserman, Stephen R., Koss, John W., Witkin, Jeffrey M., Li, Xia, Overshiner, Carl, Wafford, Keith A., Seidel, Wesley, Wang, Xu-Shan, Heinz, Beverly A., Swanson, Steven, Catlow, John T., Bedwell, David W., Monn, James A., Mitch, Charles H., and Ornstein, Paul L. Fri . "Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity". United States. https://doi.org/10.1021/acs.jmedchem.6b01119. https://www.osti.gov/servlets/purl/1340719.
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@article{osti_1340719,
title = {Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity},
author = {Chappell, Mark D. and Li, Renhua and Smith, Stephon C. and Dressman, Bruce A. and Tromiczak, Eric G. and Tripp, Allie E. and Blanco, Maria-Jesus and Vetman, Tatiana and Quimby, Steven J. and Matt, James and Britton, Thomas C. and Fivush, Adam M. and Schkeryantz, Jeffrey M. and Mayhugh, Daniel and Erickson, Jon A. and Bures, Mark G. and Jaramillo, Carlos and Carpintero, Mercedes and Diego, José Eugenio de and Barberis, Mario and Garcia-Cerrada, Susana and Soriano, José F. and Antonysamy, Stephen and Atwell, Shane and MacEwan, Iain and Condon, Bradley and Sougias, Christine and Wang, Jing and Zhang, Aiping and Conners, Kris and Groshong, Chris and Wasserman, Stephen R. and Koss, John W. and Witkin, Jeffrey M. and Li, Xia and Overshiner, Carl and Wafford, Keith A. and Seidel, Wesley and Wang, Xu-Shan and Heinz, Beverly A. and Swanson, Steven and Catlow, John T. and Bedwell, David W. and Monn, James A. and Mitch, Charles H. and Ornstein, Paul L.},
abstractNote = {As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. Here, the resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.},
doi = {10.1021/acs.jmedchem.6b01119},
journal = {Journal of Medicinal Chemistry},
number = 24,
volume = 59,
place = {United States},
year = {Fri Nov 11 00:00:00 EST 2016},
month = {Fri Nov 11 00:00:00 EST 2016}
}
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https://doi.org/10.1021/acs.jmedchem.6b01119
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    Structural insights into the activation of metabotropic glutamate receptors
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