Abstract
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
MeSH terms
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Adenosine A2 Receptor Antagonists*
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Aminopyridines / chemistry*
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Chemistry, Pharmaceutical / methods*
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Drug Design
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Haloperidol / chemistry
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Humans
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Hydrogen-Ion Concentration
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Inhibitory Concentration 50
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Models, Chemical
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Parkinson Disease / therapy
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Protein Binding
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Receptor, Adenosine A1 / chemistry
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Receptor, Adenosine A2A / chemistry
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Solubility
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Structure-Activity Relationship
Substances
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Adenosine A2 Receptor Antagonists
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Aminopyridines
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Pyrimidines
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Receptor, Adenosine A1
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Receptor, Adenosine A2A
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Haloperidol