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

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.

• Authors: Manisha Moorjani, Zhiyong Luo, Emily Lin, Binh G Vong, Yongsheng Chen, Xiaohu Zhang, Jaimie K Rueter, Raymond S Gross, Marion C Lanier, John E Tellew, John P Williams, Sandra M Lechner, Siobhan Malany, Mark Santos, María I Crespo, José-Luis Díaz, John Saunders, Deborah H Slee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 20 Pg. 5402-5 (Oct 15 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18835161 (Publication Type: Journal Article)

Chemical References

• Adenosine A2 Receptor Antagonists
• Aminopyridines
• Pyrimidines
• Receptor, Adenosine A1
• Receptor, Adenosine A2A
• Haloperidol

Topics

• 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, chemistry, pharmacology)
• Receptor, Adenosine A1 (chemistry)
• Receptor, Adenosine A2A (chemistry)
• Solubility
• Structure-Activity Relationship