Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists

被引：12
|
作者：
Yasuhara, A
Sakagami, K
Yoshikawa, R
Chaki, S
Nakamura, M
Nakazato, A
机构：
[1] Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama-shi, Saitama, 331-9530
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 10期
关键词：
mGluR2; antagonist; 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acids; synthesis; structure-activity relationship;
D O I：
10.1016/j.bmc.2005.12.061
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Chemical modification of the bicyclo[3.1.0]hexane ring C-3 position led to the discovery of 3-alkoxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 3-benzylthio-, and 3-benzylamino-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, metabotropic glutamate receptor 2 (mGluR2) antagonists. In particular, 3-(3,4-dichlorobenzyloxy)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (15ae), (IR,2S,5R,6R)-2-animo-3-(3,4-dichlorobenzylthio)-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic acid (15at), and (IR,2S,5R,6R)-2-amino-3-(N-(3,4-dichlorobenzylamino))-6-fluorobicyclo[3.1.0]hexane-2,6-carboxylic (15ba) showed high affinity for the mGluR2 receptor (15ae: K-1 = 2.51 nM, 15at: K-i = 1.96 nM, and 15ba: K-i = 3.29 nM) and potent antagonist activity for mGluR2 (15ae; IC50 = 34.21 nM, 15at; IC50 = 13.34 nM, and 15ba; IC50 = 35.96 nM). No significant agonist activity for mGluR2 was observed with 15ae, 15at, or 15ba. This paper reports on the synthesis, in vitro pharmacological profile, and structure-activity relationships (SARs) of 3-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3405 / 3420
页数：16
相关论文
共 50 条
  • [21] New synthesis of 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), a potent metabotropic receptor agonist
    Conti, P
    Kozikowski, AP
    TETRAHEDRON LETTERS, 2000, 41 (21) : 4053 - 4056
  • [22] Synthesis and evaluation of C3-and C4-substituted 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates at group II metabotropic glutamates receptors.
    Massey, SM
    Valli, MJ
    Dominguez, C
    Johnson, BG
    Andis, SL
    Wright, RA
    Schoepp, DD
    Monn, J
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 220 : U555 - U555
  • [23] Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist
    Monn, James A.
    Henry, Steven S.
    Massey, Steven M.
    Clawson, David K.
    Chen, Qi
    Diseroad, Benjamin A.
    Bhardwaj, Rajni M.
    Atwel, Shane
    Lu, Frances
    Wang, Jing
    Russell, Marijane
    Heinz, Beverly A.
    Wang, Xu-shan
    Carter, Joan H.
    Getman, Brian G.
    Adragni, Kofi
    Broad, Lisa M.
    Sanger, Helene E.
    Ursu, Daniel
    Catlow, John T.
    Swanson, Steven
    Johnson, Bryan G.
    Shaw, David B.
    McKinzie, David L.
    Hao, Junliang
    JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (06) : 2303 - 2328
  • [24] Design and synthesis of a novel series of C4-substituted 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates as potent and selective group II metabotropic glutamate receptor agonists.
    Valli, MJ
    Massey, SM
    Wright, RA
    Johnson, BG
    Andis, SL
    Schoepp, DD
    Monn, JA
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2000, 220 : U555 - U555
  • [25] Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists
    Nakazato, A
    Kumagai, T
    Sakagami, K
    Yoshikawa, R
    Suzuki, Y
    Chaki, S
    Ito, H
    Taguchi, T
    Nakanishi, S
    Okuyama, S
    JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (25) : 4893 - 4909
  • [26] Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists
    Zhang, Meng-Qi
    Zhang, Xiao-Le
    Li, Yan
    Fan, Wen-Jia
    Wang, Yong-Hua
    Hao, Ming
    Zhang, Shu-Wei
    Ai, Chun-Zhi
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2011, 12 (09): : 5999 - 6023
  • [27] In Vitro and in Vivo Evidence for a Lack of Interaction with Dopamine D2 Receptors by the Metabotropic Glutamate 2/3 Receptor Agonists 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-bicaroxylate Monohydrate (LY354740) and (-)-2-Oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic Acid (LY379268)
    Fell, Matthew J.
    Perry, Kenneth W.
    Falcone, Julie F.
    Johnson, Bryan G.
    Barth, Vanessa N.
    Rash, Karen S.
    Lucaites, Virginia L.
    Threlkeld, Penny G.
    Monn, James A.
    McKinzie, David L.
    Marek, Gerard J.
    Svensson, Kjell A.
    Nelson, David L.
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2009, 331 (03): : 1126 - 1136
  • [28] Aminobicyclo[2.2.1.]heptane dicarboxylic acids (ABHD), rigid analogs of ACPD and glutamic acid: synthesis and pharmacological activity on metabotropic receptors mGluR1 and mGluR2
    Tellier, F
    Acher, F
    Brabet, I
    Pin, JP
    Azerad, R
    BIOORGANIC & MEDICINAL CHEMISTRY, 1998, 6 (02) : 195 - 208
  • [29] Use of silyl ester and enamine protection for an efficient alternate synthesis of (1S,2S,5R,6S)-2-[(2′S)-(2′-amino)propionyl]aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid hydrochloride (LY544344•HCl)
    Fennell, Jared W.
    Semo, Michael J.
    Wirth, David D.
    Vaid, Radhe K.
    SYNTHESIS-STUTTGART, 2006, (16): : 2659 - 2664
  • [30] Synthesis, structure-activity relationships, and in vitro antibacterial and antifungal activity evaluations of novel pyrazole carboxylic and dicarboxylic acid derivatives
    Mert, Samet
    Kasimogullari, Rahmi
    Ica, Tuba
    Colak, Ferdag
    Altun, Ahmet
    Ok, Salim
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2014, 78 : 86 - 96
12345