2-Amino-6-furan-2-yl-4-substituted Nicotinonitriles as A2A Adenosine Receptor Antagonists

• Published in: Journal of medicinal chemistry 2008-08, Vol.51 (15), p.4449-4455
• Main Authors: Mantri, Monica, de Graaf, Olivier, van Veldhoven, Jacobus, Göblyös, Anikó, von Frijtag Drabbe Künzel, Jacobien K, Mulder-Krieger, Thea, Link, Regina, de Vries, Henk, Beukers, Margot W, Brussee, Johannes, IJzerman, Adriaan P
• Format: Article
• Language: English
• Subjects: Adenosine A2 Receptor Antagonists; Amines - chemistry; Animals; Cell Line; Cricetinae; Cyclic AMP - biosynthesis; Furans - chemistry; Humans; Models, Molecular; Molecular Structure; Nicotinic Acids - chemistry; Nicotinic Acids - classification; Nicotinic Acids - pharmacology; Nitriles - chemistry; Nitriles - classification; Nitriles - pharmacology; Receptor, Adenosine A2A - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701594y

A2A 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 A2A 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 A2A 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, A1, A2B, and A3. The high affinity of 44 was corroborated in a cAMP second messenger assay, yielding subnanomolar potency for this compound.