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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.


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.

SUBMITTER: Jones CK 

PROVIDER: S-EPMC3226828 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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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 CK   Engers Darren W DW   Thompson Analisa D AD   Field Julie R JR   Blobaum Anna L AL   Lindsley Stacey R SR   Zhou Ya Y   Gogliotti Rocco D RD   Jadhav Satyawan S   Zamorano Rocio R   Bogenpohl Jim J   Smith Yoland Y   Morrison Ryan R   Daniels J Scott JS   Weaver C David CD   Conn P Jeffrey PJ   Lindsley Craig W CW   Niswender Colleen M CM   Hopkins Corey R CR  

Journal of medicinal chemistry 20111019 21


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-  ...[more]

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