Progress in the design of low molecular weight thrombin inhibitors

Abstract

Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed.

1,4-Benzoxazine-3(4<i>H</i>)-ones as Potent Inhibitors of Platelet Aggregation: Design, Synthesis and Structure–Activity Relations

“…17) The reduction of the nitro group on the benzene ring gave 7-amino-4-substituted-2H-benzo[b] [1,4]oxazin-3(4H)-one 7 through the use of hydrogen catalyzed by Pd/C, followed by the amidation reaction with substituted acyl chloride at room temperature, to afford the final product 8.…”

“…The mixture was then extracted with ethyl acetate (4×40 mL). The organic layers were combined, dried over anhydrous MgSO 4 , and evaporated under vacuum to give the crude product. The residue obtained was purified by silica gel column chromatography (elute : ethyl acetate : petroleum= 1 : 10) to obtain the corresponding compound 6.…”

“…The residue obtained was purified by silica gel column chromatography (elute : ethyl acetate : petroleum= 1 : 10) to obtain the corresponding compound 6. And then to a stirred solution of 7-nitro-2H-benzo[b] [1,4] oxazin-3(4H)-one 6 (5.0 mmol, 1.0 equiv) in methanol (30 mL), 10% Pd-C (0.4 mmol, 0.08 equiv) was added to the reaction mixture at room temperature. Hydrogen was bubbled into the round bottomed flask connecting with a sealing system at atmospheric pressure at about 1 mL/min.…”

“…After hydrogenation was terminated, the brown solid 7 formed were isolated by filtration and the filtrate was distilled at vacuum without further purification. To the magnetically stirred solution of substituted 7-amino-2H-benzo[b] [1,4] oxazin-3(4H)-one 7 (5.0 mmol, 1.0 equiv) and K 2 CO 3 (7.5 mmol, 1.5 equiv) in CH 2 Cl 2 (30 mL), cooled in an ice bath, the chloroacetyl chloride (6.0 mmol, 1.2 equiv) was added dropwise slowly. The reaction mixture was stirred at room temperature and monitored by TLC.…”

“…1) Anti-thrombotic therapy agents, mainly aiming at treating thrombin platelet and thrombosis, are divided into 1) anti-platelet drugs, to prevent the coronary and cerebrovascular thrombosis from forming, such as aspirin and ticlopidine 2) ; 2) drugs against thrombin, 3,4) known as anticoagulants, including heparin and warfarin; 3) thrombolytic drugs such as fibrinolytic drugs. 5) Currently the most widely clinically applicable anti-platelet drugs are cyclooxygenase inhibitor, ADP receptor antagonists, phosphodiesterase inhibitor and GPIIb/IIIa receptor antagonist.…”