Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis |
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| Authors: | Meng-Xing Huang Yan-Quan Chen Run-Duo Liu Yue Huang Chen Zhang |
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| Affiliation: | 1.School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China; (M.-X.H.); (Y.-Q.C.); (R.-D.L.); (Y.H.);2.School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China |
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| Abstract: | 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 (T1/2) 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 (S)-4h showed outstanding metabolic stability (T1/2 = 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. |
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| Keywords: | dipyridamole phosphodiesterase metabolic stability pulmonary fibrosis molecular docking |
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