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Trifluorinated Pyrimidine-Based A 2B Antagonists: Optimization and Evidence of Stereospecific Recognition.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Oct 24; Vol. 62 (20), pp. 9315-9330. Date of Electronic Publication: 2019 Oct 04. - Publication Year :
- 2019
-
Abstract
- We report the identification of two subsets of fluorinated nonxanthine A <subscript>2B</subscript> adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA <subscript>2B</subscript> affinity ( K <subscript>i</subscript> < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA <subscript>2B</subscript> receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA <subscript>2B</subscript> receptor.
- Subjects :
- Adenosine A2 Receptor Antagonists metabolism
Binding Sites
Crystallography, X-Ray
Drug Design
Humans
Hydrogen Bonding
Ligands
Molecular Conformation
Molecular Dynamics Simulation
Protein Isoforms antagonists & inhibitors
Protein Isoforms genetics
Protein Isoforms metabolism
Pyrimidines metabolism
Receptor, Adenosine A2B genetics
Receptor, Adenosine A2B metabolism
Stereoisomerism
Structure-Activity Relationship
Adenosine A2 Receptor Antagonists chemistry
Pyrimidines chemistry
Receptor, Adenosine A2B chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31557025
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b01340