Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs

Julie L. Engers, Katrina A. Bollinger, Rebecca L. Weiner, Alice L. Rodriguez, Madeline F. Long, Megan M. Breiner, Sichen Chang, Sean R. Bollinger, Michael Bubser, Carrie K. Jones, Ryan D. Morrison, Thomas M. Bridges, Anna L. Blobaum, Colleen M. Niswender, P. Jeffrey Conn, Kyle Allen Emmitte, Craig W. Lindsley

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

Original languageEnglish
Pages (from-to)925-930
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number9
DOIs
StatePublished - 1 Jan 2017

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Pyridones
Neurology
Scaffolds
Inhibitory Concentration 50
Rats
Brain
Suspensions
Display devices
Hindlimb Suspension
Plasmas
Central Nervous System
VU0650786

Keywords

  • Negative allosteric modulator (NAM)
  • VU6010572
  • depression
  • metabotropic glutamate receptor 3 (mGlu)
  • physiochemical properties

Cite this

Engers, J. L., Bollinger, K. A., Weiner, R. L., Rodriguez, A. L., Long, M. F., Breiner, M. M., ... Lindsley, C. W. (2017). Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs. ACS Medicinal Chemistry Letters, 8(9), 925-930. https://doi.org/10.1021/acsmedchemlett.7b00249
Engers, Julie L. ; Bollinger, Katrina A. ; Weiner, Rebecca L. ; Rodriguez, Alice L. ; Long, Madeline F. ; Breiner, Megan M. ; Chang, Sichen ; Bollinger, Sean R. ; Bubser, Michael ; Jones, Carrie K. ; Morrison, Ryan D. ; Bridges, Thomas M. ; Blobaum, Anna L. ; Niswender, Colleen M. ; Conn, P. Jeffrey ; Emmitte, Kyle Allen ; Lindsley, Craig W. / Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs. In: ACS Medicinal Chemistry Letters. 2017 ; Vol. 8, No. 9. pp. 925-930.
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abstract = "Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).",
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Engers, JL, Bollinger, KA, Weiner, RL, Rodriguez, AL, Long, MF, Breiner, MM, Chang, S, Bollinger, SR, Bubser, M, Jones, CK, Morrison, RD, Bridges, TM, Blobaum, AL, Niswender, CM, Conn, PJ, Emmitte, KA & Lindsley, CW 2017, 'Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs', ACS Medicinal Chemistry Letters, vol. 8, no. 9, pp. 925-930. https://doi.org/10.1021/acsmedchemlett.7b00249

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs. / Engers, Julie L.; Bollinger, Katrina A.; Weiner, Rebecca L.; Rodriguez, Alice L.; Long, Madeline F.; Breiner, Megan M.; Chang, Sichen; Bollinger, Sean R.; Bubser, Michael; Jones, Carrie K.; Morrison, Ryan D.; Bridges, Thomas M.; Blobaum, Anna L.; Niswender, Colleen M.; Conn, P. Jeffrey; Emmitte, Kyle Allen; Lindsley, Craig W.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 9, 01.01.2017, p. 925-930.

Research output: Contribution to journalArticle

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T1 - Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs

AU - Engers, Julie L.

AU - Bollinger, Katrina A.

AU - Weiner, Rebecca L.

AU - Rodriguez, Alice L.

AU - Long, Madeline F.

AU - Breiner, Megan M.

AU - Chang, Sichen

AU - Bollinger, Sean R.

AU - Bubser, Michael

AU - Jones, Carrie K.

AU - Morrison, Ryan D.

AU - Bridges, Thomas M.

AU - Blobaum, Anna L.

AU - Niswender, Colleen M.

AU - Conn, P. Jeffrey

AU - Emmitte, Kyle Allen

AU - Lindsley, Craig W.

PY - 2017/1/1

Y1 - 2017/1/1

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AB - Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

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KW - depression

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JO - ACS Medicinal Chemistry Letters

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