RT Journal Article
T1 Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists
A1 Val García, Cristina
A1 Rodríguez García, Carlos
A1 Prieto Díaz, Rubén
A1 Crespo Gavilán, Abel
A1 Azuaje Guerrero, Jhonny Alberto
A1 Carbajales Pérez, Carlos
A1 Majellaro, María
A1 Díaz Holguín, Alejandro
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
A1 Gioé Gallo, Claudia
A1 Contino, Marialessandra
A1 Stefanachi, Angela
A1 García Mera, Xerardo
A1 Estévez Cabanas, Juan Carlos
A1 Gutiérrez de Terán, Hugo
A1 Sotelo Pérez, Eddy
AB We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure–activity and structure–selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure–activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series
PB ACS Publications
SN 0022-2623
YR 2022
FD 2022
LK http://hdl.handle.net/10347/29223
UL http://hdl.handle.net/10347/29223
LA eng
NO J. Med. Chem. 2022, 65, 3, 2091–2106
DS Minerva
RD 29 abr 2026