Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1371292 | Bioorganic & Medicinal Chemistry Letters | 2015 | 4 Pages |
A series of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives have been designed and synthesized as novel antithrombotic agents. The 4-acetoxyl substituted derivative (6g) displays very strong FXa inhibitory activity (IC50 = 0.013 μM), excellent anticoagulant effect in human plasma (2 × PT = 2.12 μM) and high selectivity to thrombin and trypsin. Docking investigation of 6g with FXa protein revealed that the pyrimidone ring of 6g formed a π–π interaction with the phenyl ring of Tyr99, and the carbonyl group in the P1 moiety formed multiple hydrogen bonds to Ser214 and Trp215. These results showed that isoxazolo[5,4-d]pyrimidin-4(5H)-one is an attractive scaffold for designing novel factor Xa inhibitors and 4-carbonyl substituted phenyl ring could be used as novel S1 binding element.
Graphical abstractIsoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives are designed as novel antithrombotic agents by selectively inhibiting coagulation factor Xa.Figure optionsDownload full-size imageDownload as PowerPoint slide