Discovery, synthesis, and structure-activity relationship development of a series of N -4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182)

Characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu 4) with oral efficacy in an antiparkinsonian animal model

Carrie K. Jones, Darren W. Engers, Analisa D. Thompson, Julie R. Field, Anna L. Blobaum, Stacey R. Lindsley, Ya Zhou, Rocco D. Gogliotti, Satyawan Jadhav, Rocio Zamorano, Jim Bogenpohl, Yoland Smith, Ryan Morrison, J. Scott Daniels, C. David Weaver, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R Hopkins

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu 4). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl) phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.

Original languageEnglish (US)
Pages (from-to)7639-7647
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number21
DOIs
StatePublished - Nov 10 2011

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Antiparkinson Agents
Structure-Activity Relationship
Rodentia
Animal Models
Catalepsy
Haloperidol
Blood-Brain Barrier
Pharmacokinetics
Brain
metabotropic glutamate receptor 4
N-(3-chloro-4-(bicyclo(2.2.1)hept-5-ene-1,3-dioxo-1H-isoindol-1-yl)phenyl)picolinamide

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery, synthesis, and structure-activity relationship development of a series of N -4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182) : Characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu 4) with oral efficacy in an antiparkinsonian animal model. / Jones, Carrie K.; Engers, Darren W.; Thompson, Analisa D.; Field, Julie R.; Blobaum, Anna L.; Lindsley, Stacey R.; Zhou, Ya; Gogliotti, Rocco D.; Jadhav, Satyawan; Zamorano, Rocio; Bogenpohl, Jim; Smith, Yoland; Morrison, Ryan; Daniels, J. Scott; Weaver, C. David; Conn, P. Jeffrey; Lindsley, Craig W.; Niswender, Colleen M.; Hopkins, Corey R.

In: Journal of Medicinal Chemistry, Vol. 54, No. 21, 10.11.2011, p. 7639-7647.

Research output: Contribution to journalArticle

Jones, CK, Engers, DW, Thompson, AD, Field, JR, Blobaum, AL, Lindsley, SR, Zhou, Y, Gogliotti, RD, Jadhav, S, Zamorano, R, Bogenpohl, J, Smith, Y, Morrison, R, Daniels, JS, Weaver, CD, Conn, PJ, Lindsley, CW, Niswender, CM & Hopkins, CR 2011, 'Discovery, synthesis, and structure-activity relationship development of a series of N -4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu 4) with oral efficacy in an antiparkinsonian animal model', Journal of Medicinal Chemistry, vol. 54, no. 21, pp. 7639-7647. https://doi.org/10.1021/jm200956q
Jones, Carrie K. ; Engers, Darren W. ; Thompson, Analisa D. ; Field, Julie R. ; Blobaum, Anna L. ; Lindsley, Stacey R. ; Zhou, Ya ; Gogliotti, Rocco D. ; Jadhav, Satyawan ; Zamorano, Rocio ; Bogenpohl, Jim ; Smith, Yoland ; Morrison, Ryan ; Daniels, J. Scott ; Weaver, C. David ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Niswender, Colleen M. ; Hopkins, Corey R. / Discovery, synthesis, and structure-activity relationship development of a series of N -4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182) : Characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu 4) with oral efficacy in an antiparkinsonian animal model. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 21. pp. 7639-7647.
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AU - Morrison, Ryan

AU - Daniels, J. Scott

AU - Weaver, C. David

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