Design and Synthesis of mGlu(2) NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Katrina A. Bollinger; Andrew S. Felts; Christopher J. Brassard; Julie L. Engers; Alice L. Rodriguez; Rebecca L. Weiner; Hyekyung P. Cho; Sichen Chang; Michael Bubser; Carrie K. Jones; Anna L. Blobaum; Colleen M. Niswender; P. Jeffrey Conn; Kyle A. Emmitte; Craig W. Lindsley

doi:10.1021/acsmedchemlett.7b00279

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Design and Synthesis of mGlu(2) NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

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Design and Synthesis of mGlu(2) NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core

Katrina A. Bollinger, Andrew S. Felts, Christopher J. Brassard, Julie L. Engers, Alice L. Rodriguez, Rebecca L. Weiner, Hyekyung P. Cho, Sichen Chang, Michael Bubser, Carrie K. Jones, …

ACS medicinal chemistry letters, Vol.8(9), pp.919-924

09/01/2017

DOI: 10.1021/acsmedchemlett.7b00279

PMCID: PMC5601377

PMID: 28947937

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Abstract

Herein, we detail the optimization of the mGlu(2) negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu(2) NAM scaffold. This new chemotype not only affords potent and selective mGlu(2) inhibition, as exemplified by VU6001966 (mGlu(2) IC50 = 78 nM, mGlu(3) IC50 > 30 mu M), but also excellent central nervous system (CNS) penetration (K-p = 1.9, K-p,K-uu = 0.78), a feature devoid in all previously disclosed mGlu(2) NAMs (K(p)s approximate to 0.3, K(p,uu)s approximate to 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu(2) PET tracer development.

Chemistry, Medicinal

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Design and Synthesis of mGlu(2) NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
Creators: Katrina A. Bollinger - Vanderbilt University
Andrew S. Felts - Vanderbilt University
Christopher J. Brassard - Vanderbilt University
Julie L. Engers - Vanderbilt University
Alice L. Rodriguez - Vanderbilt University
Rebecca L. Weiner - Vanderbilt University
Hyekyung P. Cho - Vanderbilt University
Sichen Chang - Vanderbilt University
Michael Bubser - Vanderbilt University
Carrie K. Jones - Vanderbilt University
Anna L. Blobaum - Vanderbilt University
Colleen M. Niswender - Vanderbilt University
P. Jeffrey Conn - Vanderbilt University
Kyle A. Emmitte - Vanderbilt University
Craig W. Lindsley - Vanderbilt University
Resource Type: Journal article
Publication Details: ACS medicinal chemistry letters, Vol.8(9), pp.919-924
Publisher: Amer Chemical Soc
DOI: 10.1021/acsmedchemlett.7b00279
PMID: 28947937
PMCID: PMC5601377
ISSN: 1948-5875
eISSN: 1948-5875
Number of pages: 6
Grant note: R01MH099269 / National Institute of Mental Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) U54HD083211 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) William K. Warren, Jr. and the William K. Warren Foundation
Language: English
Date published: 09/01/2017
Academic Unit: Pulmonary Medicine; Stead Family Department of Pediatrics
Record Identifier: 9984353839002771

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