rivaroxaban and anthranilamide

Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.

Topics: Animals; Anticoagulants; Arteriovenous Shunt, Surgical; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Factor Xa; Molecular Docking Simulation; Molecular Structure; ortho-Aminobenzoates; Rats; Structure-Activity Relationship; Venous Thrombosis

Factor Xa (FXa) plays a significant role in the blood coagulation cascade and is a promising target for anticoagulation drugs. Three oral FXa inhibitors have been approved by FDA for treating thrombotic diseases. In this study, 43 novel compounds were synthesized anthranilamide-based FXa inhibitors aiming to ameliorate the toxicity of traditional FXa inhibitors in clinic. The data indicated that the compounds 6a, 6a-b, 6a-e, 6k, 6k-a and 6k-b showed remarkable FXa inhibitory activity and excellent selectivity over thrombin in vitro. Selected compounds also exhibited anticoagulant activities in vitro consequently and were potent novel anti-coagulators in further.

Topics: Adult; Anticoagulants; Blood Coagulation; Computational Biology; Factor Xa; Factor Xa Inhibitors; Humans; Male; Models, Molecular; Molecular Targeted Therapy; ortho-Aminobenzoates; Plasma; Rivaroxaban; Thrombin; Thrombosis

Factor Xa (FXa) plays a significant role in the blood coagulation cascade and it has become a promising target for anticoagulation drugs. Three oral direct FXa inhibitors have been approved by the FDA for treating thrombotic diseases. By structure-activity relationship (SAR) analysis upon these FXa inhibitors, a series of novel anthranilamide-based FXa inhibitors were designed and synthesized. According to our study, compounds 1a, 1g and 1s displayed evident FXa inhibitory activity and excellent selectivity over thrombin in in vitro inhibition activities studies. Compounds 1g and 1s also exhibited pronounced anticoagulant activities in in vitro anticoagulant activity studies.

Topics: Anticoagulants; Blood Coagulation; Crystallography, X-Ray; Drug Design; Factor Xa; Factor Xa Inhibitors; Humans; Models, Molecular; Molecular Docking Simulation; ortho-Aminobenzoates; Rivaroxaban; Structure-Activity Relationship; Thrombin; Thrombosis

A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

Topics: Animals; Anticoagulants; Binding Sites; Disease Models, Animal; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Imines; Male; Models, Molecular; Molecular Structure; ortho-Aminobenzoates; Rats; Rats, Wistar; Reference Values; Serine Proteases; Serine Proteinase Inhibitors; Structure-Activity Relationship; Sulfoxides; Venous Thrombosis