TY - JOUR
T1 - Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core
AU - Bollinger, Katrina A.
AU - Felts, Andrew S.
AU - Brassard, Christopher J.
AU - Engers, Julie L.
AU - Rodriguez, Alice L.
AU - Weiner, Rebecca L.
AU - Cho, Hyekyung P.
AU - Chang, Sichen
AU - Bubser, Michael
AU - Jones, Carrie K.
AU - Blobaum, Anna L.
AU - Niswender, Colleen M.
AU - Conn, P. Jeffrey
AU - Emmitte, Kyle A.
AU - Lindsley, Craig W.
N1 - Funding Information:
The authors would also like to thank William K. Warren, Jr. and the William K. Warren Foundation who funded the William K. Warren, Jr. Chair in Medicine (to C.W.L.), and the National Institute of Mental Health for funding R01MH099269 (to K.A.E.).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/9/14
Y1 - 2017/9/14
N2 - 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.
AB - 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.
KW - CNS penetration
KW - Negative allosteric modulator (NAM)
KW - VU6001966
KW - depression
KW - metabotropic glutamate receptor 2 (mGlu)
UR - http://www.scopus.com/inward/record.url?scp=85029486744&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.7b00279
DO - 10.1021/acsmedchemlett.7b00279
M3 - Article
AN - SCOPUS:85029486744
SN - 1948-5875
VL - 8
SP - 919
EP - 924
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 9
ER -