2. Academic Validation
  3. 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

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

  • J Med Chem. 2011 Nov 10;54(21):7639-47. doi: 10.1021/jm200956q.
Carrie K Jones 1,  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
Affiliations

Affiliation

  • 1 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
PMID: 21966889 DOI: 10.1021/jm200956q
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.

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