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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Allosteric Regulation
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Animals
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Antiparkinson Agents / chemical synthesis*
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Antiparkinson Agents / pharmacokinetics
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Antiparkinson Agents / pharmacology
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Biological Availability
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CHO Cells
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Cricetinae
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Cricetulus
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Haloperidol
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Humans
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In Vitro Techniques
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Isoindoles / chemical synthesis*
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Isoindoles / pharmacokinetics
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Isoindoles / pharmacology
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Microsomes, Liver / metabolism
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Picolinic Acids / chemical synthesis*
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Picolinic Acids / pharmacokinetics
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Picolinic Acids / pharmacology
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Rats
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Receptors, Metabotropic Glutamate / physiology*
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Structure-Activity Relationship
Substances
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Antiparkinson Agents
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Isoindoles
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N-(3-chloro-4-(bicyclo(2.2.1)hept-5-ene-1,3-dioxo-1H-isoindol-1-yl)phenyl)picolinamide
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Picolinic Acids
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Receptors, Metabotropic Glutamate
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Haloperidol
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metabotropic glutamate receptor 4