SwePub - sökning: WFRF:(Majellaro Maria)

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1.	Mallo-Abreu, Ana, et al. (författare) Trifluorinated Pyrimidine-Based A(2B) Antagonists : Optimization and Evidence of Stereospecific Recognition 2019 Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:20, s. 9315-9330 Tidskriftsartikel (refereegranskat)abstract We report the identification of two subsets of fluorinated nonxanthine A(2B) 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(2B) affinity (K-i < 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(2B) 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(2B) receptor.

Mallo-Abreu, Ana, et al. (författare)
Trifluorinated Pyrimidine-Based A(2B) Antagonists : Optimization and Evidence of Stereospecific Recognition
2019
Ingår i: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:20, s. 9315-9330
Tidskriftsartikel (refereegranskat)abstract
- We report the identification of two subsets of fluorinated nonxanthine A(2B) 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(2B) affinity (K-i < 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(2B) 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(2B) receptor.

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