Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.
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 (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.
['Bollinger|Katrina A|KA|', 'Felts|Andrew S|AS|', 'Brassard|Christopher J|CJ|', 'Engers|Julie L|JL|', 'Rodriguez|Alice L|AL|', 'Weiner|Rebecca L|RL|', 'Cho|Hyekyung P|HP|', 'Chang|Sichen|S|', 'Bubser|Michael|M|', 'Jones|Carrie K|CK|', 'Blobaum|Anna L|AL|', 'Niswender|Colleen M|CM|', 'Conn|P Jeffrey|PJ|', 'Emmitte|Kyle A|KA|', 'Lindsley|Craig W|CW|']
CNS penetration Negative allosteric modulator (NAM) VU6001966 depression metabotropic glutamate receptor 2 (mGlu2)