br Introduction Thrombosis is one of

Introduction Thrombosis is one of the leading causes of deaths in the cardiovascular diseases such as myocardial infarction (MI), unstable geldanamycin and acute coronary syndrome (ACS) in developed countries [1], [2]. It is estimated that venous thromboembolism (VTE) afflicts about 1 million (1–2 per 1000) people every year in United States and about 0.1 million of them die of VTE [3]. More than one million individuals in Europe are affected by venous thromboembolic disorders each year that are responsible for at least 0.5 million deaths [4]. Thrombosis is obstruction of blood in the arterial and venous circulation. Depending upon the site of formation of thrombus, thrombosis is classified as arterial or venous thrombosis. Different types of antithrombotic drugs are used to treat both arterial and venous thrombosis depending on their pathological differences [5], [6], [7], [8], [9], [10], [11]. Arterial thrombosis is generally treated by antiplatelet agents because the condition is associated with platelet aggregation and activation induced by ruptured atherosclerotic plaque, leading to MI and ACS [12]. Obstruction of veins is in the form of deep vein thrombosis (DVT) or pulmonary embolism (PE) which can be treated by anticoagulant agents [13]. The current antithrombotic therapy includes vitamin K antagonists, coagulation enzymes’ inhibitors and heparins such as unfractionated heparins (UFHs), low molecular weight heparins (LMWHs) or fractionated heparins [6], [14], [15], [16]. Although these drugs have proved their efficacy in clinical practice but they have been found to be associated with several problems. Warfarin, a vitamin K antagonist is the most widely used antithrombotic drug. Unfortunately warfarin has a narrow therapeutic window, causes undesirable interactions with food and drugs and possesses risk of bleeding [17]. Debigatran etexilate, an oral thrombin inhibitor was found to have uncontrolled bleeding which could prove fatal [18]. Other anticoagulants like UFH, LMWHs, direct thrombin inhibitors (Argatroban, Hirudin derivatives) and indirect factor Xa (FXa) inhibitor (Fondaparinux) require parenteral administration which is responsible for clot formation at the site of injection limiting their use in clinical practice. Heparin analogs are associated with thrombocytopenia, immunological reactions and certain other serious side effects [19]. These shortcomings in the existing drugs motivate researchers to discover new orally bioavailable antithrombotic drugs with better safety profile.
Designing strategies adopted for the development of FXa inhibitors First crystal structure of FXa was reported in 1994 and till date 656 structures are available in protein data bank having 224 entries for Homosapiens [73]. After 2010 almost 33 entries of holo enzyme structures have been reported [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86] with various inhibitors (Table 1; key terms used for search criterion “coagulation Fxa + Homosapiens + 2010–2015” in PDB). As per the inputs obtained from the enzymatic studies and the available crystallographic structure of FXa, three pharmacophore units i.e. P1 moiety, P4 moiety and a central scaffold are required to be present in potential FXa inhibitors. Availability of crystal structures of FXa bound to various inhibitors has enabled researchers to identify suitable chemical moieties capable of bonding to S1 and S4 pockets of FXa using structure based drug design approach for the designing of better FXa inhibitors. Going back to early days of developments, most of the FXa inhibitors were developed by using amidine grouping as P1 and P4 motif. But due to lack of oral bioavailability and nonselectivity of amidine-based FXa inhibitors, amidine was replaced by some nonbasic functional groups as P1 motifs. Initially, efforts were made to develop orally active selective FXa inhibitors having halo or other substituted benzenes as P1 motifs. Halo derivatives particularly chloro substituted moieties (5-chlorothiophen-2-yl moiety in Rivaroxaban 1, 5-chloro-2-aminopyridine in Betrixaban 4 and Edoxaban 3, and 4-chlorobezene in Eribaxaban 5) and 4-methoxybenzenes (Apixaban 2 and Darexaban 88) have proved to be successful P1 motifs. These neutral chlorinated P1 motifs bind effectively to Tyr228 of S1 pocket by CClπ interaction and thus improve selectivity and oral bioavailability [76], [87], [88]. On the other side, amidine or bezamidine as P4 motifs were also replaced by bi- and mono-aryl motifs [75], [86], [89]. To connect the P1 and P4 moieties, various central scaffolds have been explored to form U/V or L shaped molecules [48], [90], [91], [92], [93], [94]. Different P1, P4 and central scaffolds have been identified by various research groups to develop orally active selective FXa inhibitors [28], [49], [68], [95], [96], [97]. Some of the preferred and frequently used P1 and P4 motifs, and the central scaffolds or linkers have been described below.