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Indolinone Inhibitors of ENT1 for the Treatment of Schizophrenia Gerard Rosse* Structure Guided Chemistry, Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States Adjunct Associate Professor, Department of Pharmacology and Physiology, College of Medicine, Drexel University, New College Building, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States Title:
Indolinone Inhibitors of ENT1 for the Treatment of Schizophrenia
Patent/Patent Application Number:
WO-2017076842-A1
Publication date:
May 11, 2017
Priority date:
November 6, 2015
Priority Application:
EP 2015−193355
Inventors:
Gaufreteau, D.; Kolczewski, S.; Plancher, J.-M.; Stoll, T.
Assignee Company:
F. Hoffmann-La Roche AG, Switzerland
Disease Area:
Schizophrenia
Summary:
The present application claims indolinone derivatives as inhibitors of ENT1 for the treatment of schizophrenia. One of the main claims of this application is the combination of the ENT1 inhibitors with marketed antipsychotic drug such as olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), or ziprasidone. The inhibitors of ENT1 described in this application are potentially useful in the treatment of positive and negative symptoms of schizophrenia and for a wide range of CNS diseases such as Alzheimer’s disease, Parkinson’s disease, anxiety disorders, chronic fatigue syndrome, inflammatory disease, asthma, Huntington’s disease, ADHD, amyotrophic lateral sclerosis, balance problems, and epilepsy.
Biological Target:
Equilibrative nucleoside transporter I protein (ENT1)
Important Compound Classes:
Definitions:
A is a monocyclic or bicyclic heterocycle.
Received: September 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00378 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Key Structures:
Biological Assay:
The adenosine transport activity of ENT-I mammalian cells was measured using stable cells expressing the mouse ENT-I transporter in a 96-well culture plate format. The in vivo efficacy of the compounds was evaluated in a L-687.414-induced hyperlocomotion mouse model. Some compounds of this application were also tested in SmartCube, an analytical system developed by PsychoGenics, Inc., and demonstrated similar signatures to those of atypical antipsychotics.
Pharmacological Data: (optional)
Effect of compounds on ENT1 inhibition and efficacy in L-687.414-induced hyperlocomotion mouse model
Synthesis: (optional)
Synthesis of 62 compounds is described.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest. B
DOI: 10.1021/acsmedchemlett.7b00378 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
