2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists.
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.
Mantri
Monica
M
Leiden/Amsterdam Center for Drug Research, DiVision of Medicinal Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands.
de Graaf
Olivier
O
van Veldhoven
Jacobus
J
Göblyös
Anikó
A
von Frijtag Drabbe Künzel
Jacobien K
JK
Mulder-Krieger
Thea
T
Link
Regina
R
de Vries
Henk
H
Beukers
Margot W
MW
Brussee
Johannes
J
Ijzerman
Adriaan P
AP
D058917:Adenosine A2 Receptor Antagonists; D000588:Amines / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005663:Furans / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D009570:Nitriles / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D000588:Amines; D005663:Furans; D009539:Nicotinic Acids; D009570:Nitriles; D043705:Receptor, Adenosine A2A; D000242:Cyclic AMP; C039281:furan