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

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• 作者：Bruce A. Dressman^a ; ^{DRESSMAN_BRUCE_A@lilly.com" class="auth_mail" title="E-mail the corresponding author} ; Eric G. Tromiczak^a ; Mark D. Chappell^a ; Allie E. Tripp^a ; Steven J. Quimby^a ; Tatiana Vetman^a ; Adam M. Fivush^a ; James Matt^a ; Carlos Jaramillo^b ; Renhua Li^a ; Albert Khilevich^a ; Maria-Jesus Blanco^a ; Stephon C. Smith^a ; Mercedes Carpintero^b ; José ; Eugenio de Diego^b ; Mario Barberis^b ; Susana Garcí ; a-Cerrada^b ; José ; F. Soriano^b ; Jeffrey M. Schkeryantz^a ; Jeffrey M. Witkin^a ; Keith A. Wafford^c ; Wesley Seidel^c ; Thomas Britton^a ; Carl D. Overshiner^a ; Xia Li^a ; Xu-Shan Wang^a ; Beverly A. Heinz^a ; John T. Catlow^a ; Steven Swanson^a ; David Bedwell^a ; Paul L. Ornstein^a ; Charles H. Mitch^a
• 关键词：Metabotropic glutamate ; mGlu2/3 antagonist ; Major depressive disorders ; Antidepressant
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 December 2016
• 年：2016
• 卷：26
• 期：23
• 页码：5663-5668
• 全文大小：1184 K

文摘

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 (hmGlu₂ IC₅₀ 46 ± 14.2 nM, hmGlu₃ IC₅₀ = 46.1 ± 36.2 nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1 mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10 mg/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.