title: Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors.
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 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.
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: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D065427:Factor Xa Inhibitors; C000607741:N-(5-carbamoyl-2-(4-(2-oxopyridin-1(2H)-yl)benzamido)phenyl)-3,4-dimethoxybenzamide; D011728:Pyridones; D015951:Factor Xa
keywords: 3,4-Diaminobenzoyl-based FXa inhibitors; Antithrombotic agents; FXa inhibitor; Thrombosis