Design, synthesis and evaluation of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives as antithrombotic agents

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 mu M), excellent anticoagulant effect in human plasma (2 x PT = 2.12 mu M) and high selectivity to thrombin and trypsin. Docking investigation of 6g with FXa protein revealed that the pyrimidone ring of 6g formed a pi-pi 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. (C) 2014 Elsevier Ltd. All rights reserved.