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Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T_1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound <b>(<i>S</i>)-4h</b> showed outstanding metabolic stability (T_1/2 = 67 min) in RLM, with an IC₅₀ of 332 nM against PDE5. Furthermore, some interesting structure–activity relationships (SAR) were explained with the assistance of molecular docking.