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Design and Synthesis of mGlu 2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2017 Aug 03; Vol. 8 (9), pp. 919-924. Date of Electronic Publication: 2017 Aug 03 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- Herein, we detail the optimization of the mGlu <subscript>2</subscript> negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu <subscript>2</subscript> NAM scaffold. This new chemotype not only affords potent and selective mGlu <subscript>2</subscript> inhibition, as exemplified by VU6001966 (mGlu <subscript>2</subscript> IC <subscript>50</subscript> = 78 nM, mGlu <subscript>3</subscript> IC <subscript>50</subscript> > 30 μM), but also excellent central nervous system (CNS) penetration ( K <subscript>p</subscript> = 1.9, K <subscript>p,uu</subscript> = 0.78), a feature devoid in all previously disclosed mGlu <subscript>2</subscript> NAMs ( K <subscript>p</subscript> s ≈ 0.3, K <subscript>p,uu</subscript> s ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu <subscript>2</subscript> PET tracer development.
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 8
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 28947937
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.7b00279