Abstract
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
MeSH terms
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Adenosine A2 Receptor Antagonists*
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Administration, Oral
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Animals
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Antiparkinson Agents / chemical synthesis*
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Antiparkinson Agents / pharmacology
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Catalepsy / chemically induced
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Catalepsy / prevention & control*
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Cytochrome P-450 CYP2D6 / metabolism
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Cytochrome P-450 CYP2D6 Inhibitors
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Electrophysiology
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Haloperidol / toxicity
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Humans
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Molecular Structure
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Parkinson Disease / physiopathology*
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Phenoxyacetates / chemical synthesis*
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Phenoxyacetates / chemistry
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Phenoxyacetates / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Adenosine A2 Receptor Antagonists
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Antiparkinson Agents
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Cytochrome P-450 CYP2D6 Inhibitors
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Cytochrome P-450 Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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KCNH1 protein, human
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Phenoxyacetates
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Pyrimidines
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Cytochrome P-450 Enzyme System
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Cyp3a2 protein, rat
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Cytochrome P-450 CYP2D6
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Cytochrome P-450 CYP3A
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Haloperidol