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  • br Conclusion Discovery of an

    2022-08-18


    Conclusion Discovery of an ideal orally active antithrombotic drug has remained elusive till date. Research efforts in this direction led to the discovery of numerous coagulation enzyme inhibitors including various thrombin and FXa inhibitors. Several preclinical studies have highlighted the importance of FXa as a better and effective target than thrombin because of its upstream position in the coagulation cascade. In addition to this, FXa inhibitors are reported to show nil or less bleeding risks. Better safety and superior efficacy have also been reported with FXa inhibitors over thrombin inhibitors. All these facts elevated the importance of FXa as an ideal target for the development of orally active antithrombotic agents. For the development of selective FXa inhibitors, the crystal structures of both the enzymes (FXa and thrombin) have been used. Since both these enzymes have high degree of structural similarity, computer aided drug designing techniques have been utilized to sort out the selectivity issue and to understand the structural differences in the active sites of the two enzymes. A better description of the selectivity issue has been given by Bhunia et al. [48] by taking different HMP Linker of selective thrombin, FXa and FXa-thrombin dual inhibitors into consideration. In the current review, we have systematically discussed FXa inhibitors reported by various research groups. Majority of the structural changes are reportedly carried out in three pharmacophoric units i.e. P1 moiety, P4 moiety and the central scaffold of the inhibitors. The inhibitors have been classified on the basis of chemical classes as pyrrolidine, oxazolidinone, isoxazole, anthranilamide, diamidobenzene, diamine, pyrazole, coumarin, arylsulfonamidopiperidone and tetrahydroisoquinoline based compounds reported since 2010 onward. Although a large number of compounds possess potent FXa inhibitory activity as discussed in this review, none of these compounds has entered clinical trials successfully because of their poor oral bioavailability. However, a few of the compounds (78, 88) are reported to have been selected for further clinical development. Whether these would cross the bar of clinical trials and hit the market, is a big question. Compound 78 showed an effective FXa inhibition (FXa Ki = 7 nM) and good oral bioavailability (F = 100% in rat and 65% in monkey) [74]. On the basis of binding modes of the active compounds, it could be concluded that 4-methoxyphenyl group in compounds 88 and 94, haloaromatics like 4-chlorophenyl in compound 107, 5-chloropyridine in compound 78 and 2-chlorothiophene in compounds 79 and 81 have showed good affinities for S1 pocket. Monoaryl motifs like 1-phenylpiperidin-2-one in compound 107, 1-phenylmorpholin-2-one in compounds 79 and 84, biaryl motifs like substituted biphenyls in compounds 124–126 and 1-phenylpyridin-2(1H)-one in compounds 78, 99 and 100 have showed good affinity towards S4 pocket. It can also be concluded that to maintain the desired U/V or L shaped skeletal frame of the compounds, selection of a suitable central scaffold or linker is the key to the development of potent and selective FXa inhibitors. It is hoped that this review would be helpful to the researchers for the development of selective orally active new FXa inhibitors suitable for the treatment of various thrombotic conditions involved in various cardiovascular complications.
    Acknowledgement
    Introduction Anticoagulant agents are widely used for the prevention and treatment of patients with venous or arterial thromboembolisms (Germain et al., 2015). Heparins have a rapid onset of action, but must be administered parenterally. Warfarin can be administered orally, but it has major drawbacks including the need for routine coagulation monitoring and frequent dose adjustments to maintain safe and effective levels, with a narrow therapeutic window, slow onset of action, and multiple food and drug interactions (Fisch et al., 2013, Kaatz et al., 2017, Nafee et al., 2017). Safe oral anticoagulants that are simpler and more convenient to use have therefore been sought.