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Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.


ABSTRACT: Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 ?M), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ? 0.3, Kp,uus ? 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.

SUBMITTER: Bollinger KA 

PROVIDER: S-EPMC5601377 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Herein, we detail the optimization of the mGlu<sub>2</sub> negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu<sub>2</sub> NAM scaffold. This new chemotype not only affords potent and selective mGlu<sub>2</sub> inhibition, as exemplified by VU6001966 (mGlu<sub>2</sub> IC<sub>50</sub> = 78 nM, mGlu<sub>3</sub> IC<sub>50</sub> > 30 μM), but also excellent central nervous system (CNS) penetration (<i>K</i><sub>p</sub> = 1.9, <i>K</i><sub>p,u  ...[more]

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