Journal article
Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu(3) NAMs
ACS medicinal chemistry letters, Vol.8(9), pp.925-930
09/01/2017
DOI: 10.1021/acsmedchemlett.7b00249
PMCID: PMC5601378
PMID: 28947938
Abstract
Herein, we detail the optimization of the mGlu(3) NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu(3) NAM scaffold that engenders potent and selective mGlu(3) inhibition (mGlu(3) IC50 = 245 nM, mGlu(2) IC50 > 30 mu M) with excellent central nervous system penetration (rat brain/plasma K-p = 1.2, K-p,K-uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
Details
- Title: Subtitle
- Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu(3) NAMs
- Creators
- Julie L. Engers - Vanderbilt UniversityKatrina A. Bollinger - Vanderbilt UniversityRebecca L. Weiner - Vanderbilt UniversityAlice L. Rodriguez - Vanderbilt UniversityMadeline F. Long - Vanderbilt UniversityMegan M. Breiner - Vanderbilt UniversitySichen Chang - Vanderbilt UniversitySean R. Bollinger - Vanderbilt UniversityMichael Bubser - Vanderbilt UniversityCarrie K. Jones - Vanderbilt UniversityRyan D. Morrison - Vanderbilt UniversityThomas M. Bridges - Vanderbilt UniversityAnna L. Blobaum - Vanderbilt UniversityColleen M. Niswender - Vanderbilt UniversityP. Jeffrey Conn - Vanderbilt UniversityKyle A. Emmitte - Vanderbilt UniversityCraig W. Lindsley - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.8(9), pp.925-930
- Publisher
- Amer Chemical Soc
- DOI
- 10.1021/acsmedchemlett.7b00249
- PMID
- 28947938
- PMCID
- PMC5601378
- 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
- 9984353926602771
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