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dc.contributor.authorVal García, Cristina
dc.contributor.authorRodríguez García, Carlos
dc.contributor.authorPrieto Díaz, Rubén
dc.contributor.authorCrespo Gavilán, Abel
dc.contributor.authorAzuaje Guerrero, Jhonny Alberto
dc.contributor.authorCarbajales Pérez, Carlos
dc.contributor.authorMajellaro, María
dc.contributor.authorDíaz Holguín, Alejandro
dc.contributor.authorBrea Floriani, José Manuel
dc.contributor.authorLoza García, María Isabel
dc.contributor.authorGioé Gallo, Claudia
dc.contributor.authorContino, Marialessandra
dc.contributor.authorStefanachi, Angela
dc.contributor.authorGarcía Mera, Xerardo Xusto
dc.contributor.authorEstévez Cabanas, Juan Carlos
dc.contributor.authorGutiérrez de Terán, Hugo
dc.contributor.authorSotelo, Eddy
dc.date.accessioned2022-09-16T10:54:03Z
dc.date.available2022-09-16T10:54:03Z
dc.date.issued2022
dc.identifier.citationJ. Med. Chem. 2022, 65, 3, 2091–2106
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/10347/29223
dc.description.abstractWe 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
dc.language.isoeng
dc.publisherACS Publications
dc.rights© 2022 The Authors. Published by American Chemical Society. This work is under a CC Attribution 4.0 International (CC BY 4.0)
dc.rightsAtribución 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleOptimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists
dc.typejournal article
dc.identifier.doi10.1021/acs.jmedchem.1c01636
dc.relation.publisherversionhttps://doi.org/10.1021/acs.jmedchem.1c01636
dc.type.hasVersionVoR
dc.identifier.essn1520-4804
dc.rights.accessRightsopen access
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI


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© 2022 The Authors. Published by American Chemical Society. This work is under a CC Attribution 4.0 International (CC BY 4.0)
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 © 2022 The Authors. Published by American Chemical Society. This work is under a CC Attribution 4.0 International (CC BY 4.0)





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