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 mGlu2/3antagonists. 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 mGlu2/3antagonist. 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 hmGlu2receptor 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 mGlu2antagonist 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 mGlu2IC50value.
authors.forename: Mark D
authors.identifier: 0000-0001-7442-8876
authors.initials: MD
authors.lastname: Chappell
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authors.lastname: Smith
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authors.initials: BA
authors.lastname: Dressman
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authors.lastname: Tromiczak
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authors.lastname: Tripp
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authors.lastname: Erickson
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authors.lastname: Bures
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: Carlos
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authors.lastname: Jaramillo
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: Mercedes
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authors.lastname: Carpintero
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: José Eugenio de
authors.initials: JE
authors.lastname: Diego
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Barberis
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: Susana
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authors.lastname: Garcia-Cerrada
authors.affiliation: Discovery Chemistry Synthesis Group, Centro de Investigación Lilly S.A. Avda. de la Industria , 30 Alcobendas, Madrid 28108, Spain.
authors.forename: José F
authors.initials: JF
authors.lastname: Soriano
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Stephen
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authors.lastname: Antonysamy
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Shane
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authors.lastname: Atwell
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Iain
authors.initials: I
authors.lastname: MacEwan
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Bradley
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authors.lastname: Condon
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Christine
authors.identifier: 0000-0003-3900-946X
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authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Jing
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authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Aiping
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authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Kris
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authors.lastname: Conners
authors.affiliation: Structural Biology, Lilly Biotechnology Center, Eli Lilly and Company , San Diego, California 92121, United States.
authors.forename: Chris
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authors.lastname: Groshong
authors.affiliation: Structural Biology, Eli Lilly and Company, Advanced Photon Source, Argonne National Laboratory, Building 438A, 9700 South Cass Avenue, Argonne, Illinois 60439, United States.
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authors.initials: SR
authors.lastname: Wasserman
authors.affiliation: Structural Biology, Eli Lilly and Company, Advanced Photon Source, Argonne National Laboratory, Building 438A, 9700 South Cass Avenue, Argonne, Illinois 60439, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Koss
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authors.forename: Xia
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authors.affiliation: Neuroscience Research, Eli Lilly and Company , Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, U.K. GU20 6PH.
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authors.affiliation: Neuroscience Research, Eli Lilly and Company , Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, U.K. GU20 6PH.
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authors.initials: W
authors.lastname: Seidel
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authors.lastname: Wang
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authors.initials: BA
authors.lastname: Heinz
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authors.lastname: Swanson
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.forename: David W
authors.initials: DW
authors.lastname: Bedwell
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mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: C000620392:2-amino-3-((3,4-difluorophenyl)sulfanylmethyl)-4-hydroxy-bicyclo(3.1.0)hexane-2,6-dicarboxylic acid hydrochloride; D000928:Antidepressive Agents; D003510:Cyclohexanes; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3