The Discovery of New Human Coagulation Factor XIa (FXIa) Inhibitors by Synthesis, Biological Evaluation, and Structure‐based Modeling

Abstract

Factor XIa (FXIa) is an enzyme that is activated during the earliest stage of initiation of the intrinsic pathway of the blood coagulation mechanism. In this study, we attempted to discover a new FXIa inhibitor based on structure-based molecular modeling. We found that compound 16 exhibits satisfactory predicted properties while maintaining important binding interactions with FX1a. ExperimentalDocking Study. To find a new FX1a inhibitor, we carried out a docking study of selected molecules using the § Contributed equally to this work. Procedure for the Synthesis of 4-(3-Azido-2-benzylpropanamido)-Benzoic Acid Methyl Ester (Scheme 4).2-Benzyl-3-hydroxypropanoic acid, 12 (5 g, 27.70 mmol) in DCM (200 mL) was added to t-butyldimethylsilyl chloride (9.2 g, 61.0 mmol) and imidazole (8.5 g, 124.70 mmol), stirred for 5 h, and extracted, and then ammonium chloride was added (20 mL) and again extracted with DCM (20 mL × 2). After LiOH (554 mg, 13.2 mmol) was added, the reaction mixture was stirred for 2 h, extracted with ethyl acetate (20 mL × 2), recrystallized with diethyl ether (5 mL), and 13 (8.7 mg, 99%) was obtained. And then, DIPEA (188 μL, 1.08 mmol) and PyBOP (2.3 g, 4.40 mmol) were added to 13 (1 g, 3.39 mmol) in DCM (20 mL). This solution was stirred for 6 h, and the reaction mixture was extracted with ethyl acetate (20 mL × 2). TBAF (0.5 mL, 0.48 mmol) was added Scheme 2. Synthesis of tert-butyl (1-azido-3-phenylpropan-2-yl) carbamate. (a) Ms 2 O, TEA, NaN 3 , rt. Scheme 3. Synthesis of compounds 9-11. (a) (1-Azidomethyl-3-methyl-pent-3-enyl)-carbamic acid tert-butyl ester, CuSO 4 , sodium ascorbate, DMSO:H 2 O, rt; (b) 4 M HCl, DCM, rt; (d) p-R-benzoic acid, PyBOP, DIPEA, DMF, rt. Scheme 6. Synthesis of benzyl-(2-hydroxyimino-ethyl)-carbamic acid tert-butyl ester/(2-hydroxyimino-ethyl)-phenethyl-carbamic acid tert-butyl ester. (a) Ethyl

Total Synthesis of Clavatadine B

“…Although in recent years anticoagulant drug development has targeted the inhibition of specific common pathway proteins, such as factor Xa and thrombin, FXIa may represent a new avenue for the exploration of safer methods to prevent and treat thrombosis. − Recent studies suggest that targeting FXIa may reduce the likelihood of thrombosis while preserving hemostasis. − Thus, the development of a small-molecule FXIa inhibitor into a drug capable of slowing down the effect of FXIa, thereby delaying clot formation, is promising because high FXIa expression correlates to an increased risk for stroke and venous thromboembolism. ,,− Thrombosis may also be driven by different stimuli, some of which may not include FXIa, but it is clear that more needs to be known about what causes thrombosis and how to control it safely . The exceptional potential that small-molecule FXIa inhibitors have engendered in recent years is evidenced by the prolific interest by industry and academia in their development. ,− …”