2-Amino-N-pyrimidin-4-ylacetamides as A2A Receptor Antagonists: 1. Structure−Activity Relationships and Optimization of Heterocyclic Substituents

Previously we have described a novel series of potent and selective A2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the po...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1719-1729
Main Authors: Slee, Deborah H, Chen, Yongsheng, Zhang, Xiaohu, Moorjani, Manisha, Lanier, Marion C, Lin, Emily, Rueter, Jaimie K, Williams, John P, Lechner, Sandra M, Markison, Stacy, Malany, Siobhan, Santos, Mark, Gross, Raymond S, Jalali, Kayvon, Sai, Yang, Zuo, Zhiyang, Yang, Chun, Castro-Palomino, Julio C, Crespo, María I, Prat, Maria, Gual, Silvia, Díaz, José-Luis, Saunders, John
Format: Article
Language:English
Subjects:
Acetamides - chemical synthesis
Acetamides - chemistry
Acetamides - pharmacology
Adenosine A2 Receptor Antagonists
Animals
Binding Sites
Biological and medical sciences
Cyclization
Drug Evaluation, Preclinical
Hepatocytes - drug effects
Humans
Medical sciences
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
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Summary:Previously we have described a novel series of potent and selective A2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm701185v