Indolinone Inhibitors of ENT1 for the Treatment of Schizophrenia

Kennedy, Lee, Limberis, Ly, Mak, Masatsugu, Morse, Na, Neul, Nikpur, Peters, Petroski, Renick, Sebring, Sevidal, Tabatabaei, Wen, Yan, Yoder, and ...
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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.



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