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

被引：27

作者：

Chappell, Mark D. ^{[1
]}

Li, Renhua ^{[1
]}

Smith, Stephon C. ^{[1
]}

Dressman, Bruce A. ^{[1
]}

Tromiczak, Eric G. ^{[1
]}

Tripp, Allie E. ^{[1
]}

Blanco, Maria-Jesus ^{[1
]}

Vetman, Tatiana ^{[1
]}

Quimby, Steven J. ^{[1
]}

Matt, James ^{[1
]}

Britton, Thomas C. ^{[1
]}

Fivush, Adam M. ^{[1
]}

Schkeryantz, Jeffrey M. ^{[1
]}

Mayhugh, Daniel ^{[1
]}

Erickson, Jon A. ^{[1
]}

Bures, Mark G. ^{[1
]}

Jaramillo, Carlos ^{[3
]}

Carpintero, Mercedes ^{[3
]}

Eugenio de Diego, Jose ^{[3
]}

Barberis, Mario ^{[3
]}

Garcia-Cerrada, Susana ^{[3
]}

Soriano, Jose F. ^{[3
]}

Antonysamy, Stephen ^{[4
]}

Atwell, Shane ^{[4
]}

MacEwan, Lain ^{[4
]}

Condon, Bradley ^{[4
]}

Sougias, Christine ^{[4
]}

Wang, Jing ^{[4
]}

Zhang, Aiping ^{[4
]}

Conners, Kris ^{[4
]}

Groshong, Chris ^{[4
]}

Wasserman, Stephen R. ^{[5
]}

Koss, John W. ^{[5
]}

Witkin, Jeffrey M. ^{[8
]}

Li, Xia ^{[8
]}

Overshiner, Carl ^{[8
]}

Wafford, Keith A. ^{[6
]}

Seidel, Wesley ^{[6
]}

Wang, Xu-Shan ^{[2
]}

Heinz, Beverly A. ^{[2
]}

Swanson, Steven ^{[7
]}

Catlow, John T. ^{[7
]}

Bedwell, David W. ^{[7
]}

Monn, James A. ^{[1
]}

Mitch, Charles H. ^{[1
]}

Ornstein, Paul L. ^{[1
]}

机构：

[1] Eli Lilly & Co, Discovery Chem Res & Technol Med Chem, Indianapolis, IN 46285 USA

[2] Eli Lilly & Co, Quantitat Biol, Indianapolis, IN 46285 USA

[3] Ctr Invest Lilly SA, Discovery Chem Synth Grp, Avda Ind,30 Alcobendas, Madrid 28108, Spain

[4] Eli Lilly & Co, Lilly Biotechnol Ctr, Struct Biol, San Diego, CA 92121 USA

[5] Eli Lilly & Co, Adv Photon Source, Argonne Natl Lab, Struct Biol, Bldg 438A,9700 South Cass Ave, Argonne, IL 60439 USA

[6] Eli Lilly & Co, Neurosci Res, Erl Wood Manor, Sunninghill Rd, Windlesham GU20 6PH, Surrey, England

[7] Eli Lilly & Co, Drug Disposit, Indianapolis, IN 46285 USA

[8] Eli Lilly & Co, Neurosci Res, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 24期

关键词：

GROUP-II; PHARMACOLOGICAL CHARACTERIZATION; MGLU2/3; AGONIST; TERM DEPRESSION; PERFORANT PATH; DENTATE GYRUS; ANIMAL-MODELS; KETAMINE; EFFICACY; ACTIVATION;

D O I：

10.1021/acs.jmedchem.6b01119

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu(2/3)) receptors, we have incorporated substitution at the C3 and C4 positions of the (1.5,2R,SR,6R)-2-amino-bicydo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate rnGlu(2/3) antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (15,2R,35,4S,A6R)-2-amino-3-[(3,4-difluorophenyl) sulfanylmethyl]-4-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid hydrochloride (LY3020371 center dot HCl, 19f), a potent, selective, and maximally efficacious mGlu(2/3) antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu(2)) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu(2) receptor protein. 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 mGlu(2) 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 mGlu(2) IC50 value.

引用

页码：10974 / 10993

页数：20

共 65 条

[1] Ketamine for Depression: Where Do We Go from Here?
Aan Het Rot, Marije
Zarate, Carlos A., Jr.
Charney, Dennis S.
Mathew, Sanjay J.
[J]. BIOLOGICAL PSYCHIATRY, 2012, 72 (07) : 537 - 547
[2] [Anonymous], MOL OP ENV MOE VERS
[3] Antidepressant effects of ketamine in depressed patients
Berman, RM
Cappiello, A
Anand, A
Oren, DA
Heninger, GR
Charney, DS
Krystal, JH
[J]. BIOLOGICAL PSYCHIATRY, 2000, 47 (04) : 351 - 354
[4] ACID AMIDE-REACTIONS L - ORTHO-AMIDES .I. SYNTHESIS AND PROPERTIES OF AMIDE ACETALES AND AMINALESTERS
BREDERECK, H
SIMCHEN, G
REBSDAT, S
KANTLEHNER, W
HORN, P
WAHL, R
HOFFMANN, H
GRIESHABER, P
[J]. CHEMISCHE BERICHTE-RECUEIL, 1968, 101 (01): : 41 - +
[5] Regulation of neurotransmitter release by metabotropic glutamate receptors
Cartmell, J
Schoepp, DD
[J]. JOURNAL OF NEUROCHEMISTRY, 2000, 75 (03) : 889 - 907
[6] MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity
Chaki, S
Yoshikawa, R
Hirota, S
Shimazaki, T
Maeda, M
Kawashima, N
Yoshimizu, T
Yasuhara, A
Sakagami, K
Okuyama, S
Nakanishi, S
Nakazato, A
[J]. NEUROPHARMACOLOGY, 2004, 46 (04) : 457 - 467
[7] Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia
Chaki, Shigeyuki
[J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 2010, 639 (1-3) : 59 - 66
[8] Pharmacology and functions of metabotropic glutamate receptors
Conn, PJ
Pin, JP
[J]. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1997, 37 : 205 - 237
[9] HIGHLY ENANTIOSELECTIVE BORANE REDUCTION OF KETONES CATALYZED BY CHIRAL OXAZABOROLIDINES - MECHANISM AND SYNTHETIC IMPLICATIONS
COREY, EJ
BAKSHI, RK
SHIBATA, S
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1987, 109 (18) : 5551 - 5553
[10] The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection
Corti, Corrado
Battaglia, Giuseppe
Molinaro, Gemma
Riozzi, Barbara
Pittaluga, Anna
Corsi, Mauro
Mugnaini, Manolo
Nicoletti, Ferdinando
Bruno, Valeria
[J]. JOURNAL OF NEUROSCIENCE, 2007, 27 (31) : 8297 - 8308

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