Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors

• Published in: European journal of medicinal chemistry Vol. 101; pp. 41 - 51
• Main Authors: Yang, Jiabin, Su, Guoqiang, Ren, Yu, Chen, Yang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 28.08.2015
• Subjects: 3,4-Diaminobenzoyl-based FXa inhibitors; Animals; Antithrombotic agents; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Crystallography, X-Ray; Dose-Response Relationship, Drug; Factor Xa - metabolism; Factor Xa Inhibitors - chemical synthesis; Factor Xa Inhibitors - chemistry; Factor Xa Inhibitors - pharmacology; FXa inhibitor; Humans; Models, Molecular; Molecular Structure; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Rabbits; Rats; Structure-Activity Relationship; Thrombosis; Antithrombotic agents; FXa inhibitor; Thrombosis; 3,4-Diaminobenzoyl-based FXa inhibitors
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2015.06.012

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 structure–activity 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. A series of 3,4-diaminobenzoyl compounds have been designed and synthesized as novel antithrombotic agents. Thereinto, compound 7b is a highly potent, selective FXa inhibitor with excellent in vivo antithrombotic activity. [Display omitted] •3,4-Diaminobenzoyl-based FXa inhibitors were designed and synthesized.•Most of them possess good anticoagulant potency.•Thereinto, 7b is an in vivo highly antithrombotic, selective FXa inhibitor.