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Search: id:"swepub:oai:DiVA.org:uu-477758" > Optimization of 2-A...

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  • Val, CristinaUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A(1) Antagonists

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-01-22
  • American Chemical Society (ACS),2022
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-477758
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-477758URI
  • https://doi.org/10.1021/acs.jmedchem.1c01636DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A(1)AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarily 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 R-4 and R-6 of the pyrimidine core but most importantly the prominent role to the unprecedented A(1)AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A(1) and A(2A)ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.

Subject headings and genre

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  • Rodriguez-Garcia, CarlosUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Prieto-Diaz, RubenUppsala universitet,Beräkningsbiologi och bioinformatik,Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Crespo, AbelUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Azuaje, JhonnyUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Carbajales, CarlosUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Majellaro, MariaUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Diaz-Holguin, AlejandroUppsala universitet,Institutionen för cell- och molekylärbiologi (author)
  • Brea, Jose M.Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain. (author)
  • Isabel Loza, MariaUniv Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain. (author)
  • Gioe-Gallo, ClaudiaUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Contino, MarialessandraUniv Bari ALDO MORO, Dipartimento Farm Sci Farmaco, I-70125 Bari, Italy. (author)
  • Stefanachi, AngelaUniv Bari ALDO MORO, Dipartimento Farm Sci Farmaco, I-70125 Bari, Italy. (author)
  • Garcia-Mera, XerardoUniv Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Estevez, Juan C.Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain. (author)
  • Gutiérrez-de-Terán, HugoUppsala universitet,Beräkningsbiologi och bioinformatik(Swepub:uu)hugut367 (author)
  • Sotelo, EddyUniv Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain. (author)
  • Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CiQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Dept Quim Organ, Santiago De Compostela 15782, Spain.Beräkningsbiologi och bioinformatik (creator_code:org_t)

Related titles

  • In:Journal of Medicinal Chemistry: American Chemical Society (ACS)65:3, s. 2091-21060022-26231520-4804

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