Miranda Pastoriza, DaríoBernárdez Alfaya, RodrigoAzuaje Guerrero, Jhonny AlbertoPrieto Díaz, RubénMajellaro, MariaTamhankar, Ashish V.Koenekoop, LucienGonzález García, AlejandroGioé Gallo, ClaudiaMallo-Abreu, AnaBrea Floriani, José ManuelLoza García, María IsabelGarcía Rey, AitorGarcía Mera, XerardoGutiérrez de Terán, HugoSotelo Pérez, Eddy2022-09-162022-09-162022ACS Med. Chem. Lett. 2022, 13, 2, 243–2491948-5875http://hdl.handle.net/10347/29225A library of potent and highly A3AR selective pyrimidine-based compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposeseng© 2022 The Authors. Published by American Chemical Society. This work is under a CC Attribution 4.0 International (CC BY 4.0)Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/A3 Adenosine receptorsAdenosine antagonistsPyrimidinesUgi reactionMulticomponent reactionsjournal article10.1021/acsmedchemlett.1c00598open access