2,6-Diaryl-4-acylaminopyrimidines as potent and selective adenosine A(2A) antagonists with improved solubility and metabolic stability

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 wi...

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Published in:Bioorganic & medicinal chemistry letters 2008-10, Vol.18 (20), p.5402
Main Authors: Moorjani, Manisha, Luo, Zhiyong, Lin, Emily, Vong, Binh G, Chen, Yongsheng, Zhang, Xiaohu, Rueter, Jaimie K, Gross, Raymond S, Lanier, Marion C, Tellew, John E, Williams, John P, Lechner, Sandra M, Malany, Siobhan, Santos, Mark, Crespo, María I, Díaz, José-Luis, Saunders, John, Slee, Deborah H
Format: Article
Language:English
Subjects:
Adenosine A2 Receptor Antagonists
Aminopyridines - chemistry
Chemistry, Pharmaceutical - methods
Drug Design
Haloperidol - chemistry
Humans
Hydrogen-Ion Concentration
Inhibitory Concentration 50
Models, Chemical
Parkinson Disease - therapy
Protein Binding
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Receptor, Adenosine A1 - chemistry
Receptor, Adenosine A2A - chemistry
Solubility
Structure-Activity Relationship
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Summary: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.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2008.09.048