Abstract
Background: A3AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A3AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A3AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A3AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure–activity and structure–selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.
Financial & competing interests disclosure
This work was financially supported by the Galician Government (Spain), grant: 09CSA016234PR, the Swedish Research Council, grant: 521-2014-2118, and by the Swedish strategic research program eSSENCE. J Azuaje thanks FUNDAYACUCHO (Venezuela) and Diputación da Coruña (Galicia, Spain) for research grants. J Azuaje, H Gutiérrez-de-Terán and E Sotelo participated in the European COST Action CM1207 (GLISTEN). The authors have no other relevant affiliations orfinancial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.