Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 21, Pages 7639-7647Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm200956q
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Funding
- National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
- Micheal J. Fox Foundation
- Vanderbilt Department of Pharmacology
- Vanderbilt Institute of Chemical Biology
- NIH/MLPCN [5U54MH08465-02]
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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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