Multicomponent Assembly of Diverse Pyrazin-2(1<i>H</i>)‑one Chemotypes

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2­(1<i>H</i>)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner

Multicomponent Assembly of Diverse Pyrazin-2(1<i>H</i>)‑one Chemotypes

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2­(1<i>H</i>)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner

Three-Component Assembly of Structurally Diverse 2‑Aminopyrimidine-5-carbonitriles

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization

Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes

Three novel families of A_2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2­(1<i>H</i>)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A_2B ligand that exhibits complete selectivity toward A₁, A_2A, and A₃ receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A_2A receptor

Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes

Three novel families of A_2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2­(1<i>H</i>)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A_2B ligand that exhibits complete selectivity toward A₁, A_2A, and A₃ receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A_2A receptor

Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)‑ones As a Novel Class of Potent and Selective A_2B Adenosine Receptor Antagonists

We describe the discovery and optimization of 3,4-dihydropyrimidin-2­(1<i>H</i>)-ones as a novel family of (nonxanthine) A_2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure–activity and structure–selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA_2B AdoR affinity and remarkable selectivity profiles