title: Design, synthesis and evaluation of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives as antithrombotic agents.
abstract: 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=0.013μM), excellent anticoagulant effect in human plasma (2×PT=2.12μM) 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.
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Nanjing Zhongrui Pharmaceutical Co., Ltd, Nanjing, Jiangsu 211100, PR China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Su
authors.affiliation: Nanjing Zhongrui Pharmaceutical Co., Ltd, Nanjing, Jiangsu 211100, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China. Electronic address: yc@seu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010080:Oxazoles; D011728:Pyridones; C508120:oxazolopyridinone; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa
keywords: Antithrombotic agent; Docking; Factor Xa; Isoxazolo[5,4-d]pyrimidin-4(5H)-one