2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists.

Article Details

Citation

Copy to clipboard

Mantri M, de Graaf O, van Veldhoven J, Goblyos A, von Frijtag Drabbe Kunzel JK, Mulder-Krieger T, Link R, de Vries H, Beukers MW, Brussee J, Ijzerman AP

2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists.

J Med Chem. 2008 Aug 14;51(15):4449-55. doi: 10.1021/jm701594y. Epub 2008 Jul 19.

PubMed ID

18637670 [ View in PubMed

]

Abstract

A 2A adenosine receptor antagonists usually have bi- or tricyclic N aromatic systems with varying substitution patterns to achieve desired receptor affinity and selectivity. Using a pharmacophore model designed by overlap of nonxanthine type of previously known A 2A antagonists, we synthesized a new class of compounds having a 2-amino nicotinonitrile core moiety. From our data, we conclude that the presence of at least one furan group rather than phenyl is beneficial for high affinity on the A 2A adenosine receptor. Compounds 39 (LUF6050) and 44 (LUF6080) of the series had K i values of 1.4 and 1.0 nM, respectively, with reasonable selectivity toward the other adenosine receptor subtypes, A 1, A 2B, and A 3. The high affinity of 44 was corroborated in a cAMP second messenger assay, yielding subnanomolar potency for this compound.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-{2-[(7-amino-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino]ethyl}phenol	Adenosine receptor A2a	Ki (nM)	0.8	N/A	N/A	Details