2. Academic Validation
  3. Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

  • J Med Chem. 2022 Feb 10;65(3):2091-2106. doi: 10.1021/acs.jmedchem.1c01636.
Cristina Val 1 2,  Carlos Rodríguez-García 1 2,  Rubén Prieto-Díaz 1 2 3,  Abel Crespo 1 2,  Jhonny Azuaje 1 2,  Carlos Carbajales 1 2,  Maria Majellaro 1 2,  Alejandro Díaz-Holguín 3,  José M Brea 4,  Maria Isabel Loza 4,  Claudia Gioé-Gallo 1 2,  Marialessandra Contino 5,  Angela Stefanachi 5,  Xerardo García-Mera 2,  Juan C Estévez 1,  Hugo Gutiérrez-de-Terán 3,  Eddy Sotelo 1 2
Affiliations

Affiliations

  • 1 Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 2 Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 3 Department of Cell and Molecular Biology, Uppsala University, Uppsala 75124, Sweden.
  • 4 Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 5 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, via Orabona 4, Bari 70125, Italy.
PMID: 35068155 DOI: 10.1021/acs.jmedchem.1c01636
Abstract

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.

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