Abstract
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
MeSH terms
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Adenosine A1 Receptor Antagonists / chemical synthesis*
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Adenosine A1 Receptor Antagonists / pharmacokinetics
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Adenosine A1 Receptor Antagonists / pharmacology
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Adenosine A2 Receptor Antagonists / chemical synthesis*
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Adenosine A2 Receptor Antagonists / pharmacokinetics
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Adenosine A2 Receptor Antagonists / pharmacology
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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 / pharmacokinetics
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Antiparkinson Agents / pharmacology
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Callithrix
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Disease Models, Animal
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Female
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Indenes / chemical synthesis*
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Indenes / pharmacokinetics
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Indenes / pharmacology
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Macaca fascicularis
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Male
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Mice
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Mice, Inbred BALB C
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Parkinson Disease / metabolism*
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, Adenosine A2A / physiology*
Substances
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2-amino-4-phenyl-8-(pyrrolidin-1-ylmethyl)-5H-indeno(1,2-d)pyrimidin-5-one
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Adenosine A1 Receptor Antagonists
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Adenosine A2 Receptor Antagonists
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Antiparkinson Agents
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Indenes
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Pyrimidines
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Receptor, Adenosine A2A