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Yang J.,Nanjing Southeast University | Su G.,Nanjing Zhongrui Pharmaceutical Co. | Ren Y.,Nanjing Zhongrui Pharmaceutical Co. | Chen Y.,Nanjing Southeast University
European Journal of Medicinal Chemistry | Year: 2015

Abstract The coagulation factor Xa (FXa) plays a central role in the blood coagulation cascade. Recent studies have shown that FXa is a particularly attractive target for the development of oral antithrombotic agents. In view of the excellent pharmaceutical properties of 1,2-phenylenediamine-based FXa inhibitors and the reported structureeactivity relationship (SAR) analysis of FXa inhibitors, we designed and synthesized a series of 3,4-diaminobenzoyl-based FXa inhibitors. Intensive SAR studies on this new series led to the discovery of 3,4-dimethoxyl substituted compound 7b. 7b is a highly potent, selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. © 2015 Elsevier Masson SAS.


Yang J.,Nanjing Southeast University | Su G.,Nanjing Zhongrui Pharmaceutical Co. | Ren Y.,Nanjing Zhongrui Pharmaceutical Co. | Chen Y.,Nanjing Southeast University
Research on Chemical Intermediates | Year: 2015

A series of 3-(1H-imidazo[4,5-c]pyridin-2-yl)-1,5-diarylpyridin-2(1H)-one derivatives were designed and synthesized as potential anticoagulant agents. The 1,5-diarylpyridin-2(1H)-ones, key intermediates of these anticoagulants, were synthesized by a simple reaction of 2-aryl vinamidinium salts with ethyl 3-oxo-3-(arylamino)propanoate derivatives. The prothrombin time in canine blood showed that amino and hydroxymethyl derivatives therein possess obvious anticoagulant abilities (PT = 17.07 s). © 2015 Springer Science+Business Media Dordrecht.


Yang J.,Nanjing Southeast University | Su G.,Nanjing Zhongrui Pharmaceutical Co. | Ren Y.,Nanjing Zhongrui Pharmaceutical Co. | Chen Y.,Nanjing Southeast University
Bioorganic and Medicinal Chemistry Letters | Year: 2015

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. © 2014 Elsevier Ltd. All rights reserved.


Yang J.,Nanjing Southeast University | Su G.,Nanjing Zhongrui Pharmaceutical Co. | Ren Y.,Nanjing Zhongrui Pharmaceutical Co. | Chen Y.,Nanjing Southeast University
Journal of Chemical Research | Year: 2015

The mechanism of formation of a pyridin-2(1H )-one synthesised from vinamidinium salts and cyanoacetamide derivatives is illustrated through the preparation and characterisation of a key intermediate.


Yang J.,Nanjing Southeast University | Su G.,Nanjing Zhongrui Pharmaceutical Co. | Ren Y.,Nanjing Zhongrui Pharmaceutical Co. | Chen Y.,Nanjing Southeast University
Tetrahedron | Year: 2014

A one step, direct method for the synthesis of 1,5-diaryl pyridin-2(1H)-one derivatives by condensation of 2-aryl vinamidinium salts with N-aryl cyanoacetamides has been developed. This method can conveniently provide the corresponding 1,5-diaryl pyridin-2(1H)-one derivatives with various substituents in good yields and overcome the drawbacks of existing methods such as poor substrate scope, heavy metal pollution, and low yields. The formation mechanism of the products was illustrated. © 2014 Elsevier Ltd.

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