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.

[1]  J. Topliss,et al.  Utilization of operational schemes for analog synthesis in drug design. , 1972, Journal of medicinal chemistry.

[2]  H. Midorikawa,et al.  A Simple Method for the Preparation of 2-Amino-4-aryl-3-cyanopyridines by the Condensation of Malononitrile with Aromatic Aldehydes and Alkyl Ketones in the Presence of Ammonium Acetate , 1980 .

[3]  B. Fredholm,et al.  Comparison of CGS 15943, ZM 241385 and SCH 58261 as antagonists at human adenosine receptors , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[4]  J. Moreau,et al.  Central adenosine A2A receptors: an overview , 1999, Brain Research Reviews.

[5]  S. Bhagwat,et al.  Structure-activity studies of 5-substituted pyridopyrimidines as adenosine kinase inhibitors. , 2001, Bioorganic & medicinal chemistry letters.

[6]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[7]  G. Spalluto,et al.  7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility. , 2002, Journal of medicinal chemistry.

[8]  C. Dourish,et al.  Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson’s disease , 2003, Neurology.

[9]  Pier Andrea Borea,et al.  Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists. , 2003, Journal of medicinal chemistry.

[10]  Erratum to “Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1” , 2003 .

[11]  H. V. van Vlijmen,et al.  Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A2A receptor antagonists. , 2004, Journal of medicinal chemistry.

[12]  T. Engber,et al.  Studies on adenosine A2a receptor antagonists: comparison of three core heterocycles. , 2004, Bioorganic & medicinal chemistry letters.

[13]  C. Müller,et al.  Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease. , 2004, The Journal of organic chemistry.

[14]  Synthesis and SAR Evaluation of 1,2,4-Triazoles as A2A Receptor Antagonists. , 2004 .

[15]  John P Caldwell,et al.  2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs as adenosine A2A antagonists: the successful reduction of hERG activity. Part 2. , 2005, Bioorganic & medicinal chemistry letters.

[16]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[17]  B. Neustadt,et al.  The discovery and synthesis of novel adenosine receptor (A(2A)) antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[18]  Giovanni Piersanti,et al.  2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization. , 2005, Journal of medicinal chemistry.

[19]  T. Engber,et al.  Synthesis of alkyne derivatives of a novel triazolopyrazine as A(2A) adenosine receptor antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[20]  E. Bastia,et al.  Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease. , 2005, Pharmacology & therapeutics.

[21]  D. Tulshian,et al.  2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs: highly potent, orally active, adenosine A2A antagonists. Part 1. , 2005, Bioorganic & medicinal chemistry letters.

[22]  Synthesis of [1,2,4]Triazolo[1,5-a]pyrazines as Adenosine A2A Receptor Antagonists. , 2006 .

[23]  K. Jacobson,et al.  Adenosine receptors as therapeutic targets , 2006, Nature Reviews Drug Discovery.

[24]  Thomas Bäck,et al.  The Molecule Evoluator. An Interactive Evolutionary Algorithm for the Design of Drug-Like Molecules , 2006, J. Chem. Inf. Model..

[25]  R. Gillespie,et al.  Identification of non-furan containing A2A antagonists using database mining and molecular similarity approaches. , 2006, Bioorganic & medicinal chemistry letters.

[26]  S. Soelaiman,et al.  Characterization of the potency, selectivity, and pharmacokinetic profile for six adenosine A2A receptor antagonists , 2007, Naunyn-Schmiedeberg's Archives of Pharmacology.

[27]  Eric-Wubbo Lameijer,et al.  Designing active template molecules by combining computational de novo design and human chemist's expertise. , 2007, Journal of medicinal chemistry.

[28]  3D‐Pharmacophore Models for Selective A2A and A2B Adenosine Receptor Antagonists. , 2007 .