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

Katrina A. Bollinger; Andrew S. Felts; Christopher J. Brassard; Julie L. Engers; Alice L. Rodriguez; Rebecca L. Weiner; Hyekyung P. Cho; Sichen Chang; Michael Bubser; Carrie K. Jones; Anna L. Blobaum; Colleen M. Niswender; P. Jeffrey Conn; Kyle A. Emmitte; Craig W. Lindsley

doi:10.1021/acsmedchemlett.7b00279

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

Katrina A. Bollinger, Andrew S. Felts, Christopher J. Brassard, Julie L. Engers, Alice L. Rodriguez, Rebecca L. Weiner, Hyekyung P. Cho, Sichen Chang, Michael Bubser, Carrie K. Jones, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Kyle A. Emmitte, Craig W. Lindsley

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25 Scopus citations

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 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.

Original language	English
Pages (from-to)	919-924
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	9
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00279
State	Published - 14 Sep 2017

Keywords

CNS penetration
Negative allosteric modulator (NAM)
VU6001966
depression
metabotropic glutamate receptor 2 (mGlu)

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10.1021/acsmedchemlett.7b00279

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Bollinger, K. A., Felts, A. S., Brassard, C. J., Engers, J. L., Rodriguez, A. L., Weiner, R. L., Cho, H. P., Chang, S., Bubser, M., Jones, C. K., Blobaum, A. L., Niswender, C. M., Conn, P. J., Emmitte, K. A., & Lindsley, C. W. (2017). Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core. ACS Medicinal Chemistry Letters, 8(9), 919-924. https://doi.org/10.1021/acsmedchemlett.7b00279

@article{f630420aabe5406ba94fa9227bcb0cc9,

title = "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 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.",

keywords = "CNS penetration, Negative allosteric modulator (NAM), VU6001966, depression, metabotropic glutamate receptor 2 (mGlu)",

author = "Bollinger, {Katrina A.} and Felts, {Andrew S.} and Brassard, {Christopher J.} and Engers, {Julie L.} and Rodriguez, {Alice L.} and Weiner, {Rebecca L.} and Cho, {Hyekyung P.} and Sichen Chang and Michael Bubser and Jones, {Carrie K.} and Blobaum, {Anna L.} and Niswender, {Colleen M.} and Conn, {P. Jeffrey} and Emmitte, {Kyle A.} and Lindsley, {Craig W.}",

note = "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: {\textcopyright} 2017 American Chemical Society.",

year = "2017",

month = sep,

day = "14",

doi = "10.1021/acsmedchemlett.7b00279",

language = "English",

volume = "8",

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journal = "ACS Medicinal Chemistry Letters",

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Bollinger, KA, Felts, AS, Brassard, CJ, Engers, JL, Rodriguez, AL, Weiner, RL, Cho, HP, Chang, S, Bubser, M, Jones, CK, Blobaum, AL, Niswender, CM, Conn, PJ, Emmitte, KA & Lindsley, CW 2017, 'Design and Synthesis of mGlu₂ NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core', ACS Medicinal Chemistry Letters, vol. 8, no. 9, pp. 919-924. https://doi.org/10.1021/acsmedchemlett.7b00279

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)

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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 -

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

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Keywords

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