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

摘要

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 μM), but also excellent central nervous system (CNS) penetration (K_p = 1.9, K_p,uu = 0.78), a feature devoid in all previously disclosed mGlu₂ NAMs (K_ps ≈ 0.3, K_p,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu₂ PET tracer development.]]>