Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression.

Autor: Dressman BA; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA. Electronic address: DRESSMAN_BRUCE_A@lilly.com., Tromiczak EG; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Chappell MD; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Tripp AE; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Quimby SJ; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Vetman T; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Fivush AM; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Matt J; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Jaramillo C; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., Li R; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Khilevich A; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Blanco MJ; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Smith SC; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Carpintero M; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., de Diego JE; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., Barberis M; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., García-Cerrada S; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., Soriano JF; Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain., Schkeryantz JM; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Witkin JM; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Wafford KA; Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK., Seidel W; Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK., Britton T; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Overshiner CD; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Li X; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Wang XS; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Heinz BA; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Catlow JT; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Swanson S; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Bedwell D; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Ornstein PL; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA., Mitch CH; Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Dec 01; Vol. 26 (23), pp. 5663-5668. Date of Electronic Publication: 2016 Oct 25.
DOI: 10.1016/j.bmcl.2016.10.067
Abstrakt: Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu 2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu 2 IC 50 46±14.2nM, hmGlu 3 IC 50 =46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu 2/3 receptors both in vitro and in vivo.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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