br Drug design Over the past decades the development of

Drug design Over the past decades, the development of synthetic, direct fXa inhibitors has undergone four phase. Although these fXa inhibitors possess various scaffolds, most of them bind to the active site in a characteristic l-shaped conformation. In other word, they have a three-component system including a central scaffold and two hydrophobic fragments (P1 and P4) which provides a similar non-linear geometry considered to play a crucial role in fXa recognition. Many novel fXa inhibitors such as apixaban and rivaroxaban adopt very similar conformations including the length and orientation of P1 and P4. As shown in Fig. 2A, apixaban (pink, PDB code 2P16) and rivaroxaban (green, PDB code 2w26) bind with fXa in a quite similar conformational space. Although their scaffolds could not be overlaid and formed significantly different interactions with fXa, their aromatic rings in P4 fragments superimposed very well, and length and orientation of P1 and P4 are also very similar. In addition, the binding conformation of betrixaban with fXa was predicted by glide in Schrodinger 2009 which has been demonstrated to successfully predict the binding modes of many reported inhibitors to fXa. It was also found that the P1 and P4 fragments of betrixaban and rivaroxaban, especially P1 group, adopted very similar conformations (Fig. 2B). Based on these modeling and findings, it was postulated that the highly basic amidine group of betrixaban can be replaced by less basic P4 moieties of rivaroxaban, apixaban and edoxaban. Meanwhile, the P1 fragment of betrixaban also can be changed to other substituted aromatic or heteroaromatic rings. As a result, a novel series of anthranilamide derivatives were designed (Fig. 3), synthesized and evaluated for their fXa inhibitory activity.
Results and discussion
Conclusion In summary, a series of novel anthranilamide derivatives were designed and synthesized as potent and selective fXa inhibitors by utilizing structure-based design strategies. Most of the target compounds displayed some degree of fXa inhibitory activity. Of these molecules, the Pridinol Methanesulfonate 16g was found to possess the best fXa inhibition with an IC50 value of 3.5 nM, significant selectivity against other serine protease, and pronounced in vitro and in vivo anticoagulant efficacy. The bleeding risk evaluation exhibited that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. The pharmacokinetic profiles of 16g were studied and presented favorable results. In addition, in MTT assay, 16g displayed significant ability to improve hypoxia–reoxygenation-induced H9C2 cell viability. The effects of 16g on myocardial injury are being evaluated by our lab and will be reported in due course.
Experimental section
Acknowledgment This research was supported by the Natural Science Foundation of Jiangsu Province (No. BK 20141349) and the China National Key Hi-tech Innovation Project for the R&D of Novel Drugs (No. 2013ZX09301303-002).
Introduction Venous thromboembolism (VTE) is a common complication of cancer guanine has a significant impact on morbidity and mortality in cancer patients [1]. Cancer patients have a four to seven-fold greater risk of VTE compared to patients without cancer [2], [3]. Among VTE patients, cancer patients account for as much as 20% of the total burden of VTE [4]. In Japan, Nakamura et al. showed that a history of cancer was the most common risk factor of VTE, present in 27.0% of VTE patients [5], [6]. Kabuki et al. also showed a high prevalence of malignant tumors (26%) in patients with acute VTE [7]. Furthermore, the risk of recurrent VTE while on anticoagulant treatment is particularly high in patients with cancer, as is the risk of bleeding complications [8], [9], [10], [11]. Using a Japanese healthcare database, Nakamura et al. also demonstrated that malignant disease was a predictor of recurrent VTE as well as bleeding [12]. Low-molecular-weight heparins (LMWHs) have been shown to be more effective than and as safe as conventional anticoagulation with initial LMWH followed by vitamin K antagonists [13], [14], [15]. Several guidelines from the USA and Europe, namely, from the American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), American College of Chest Physicians (ACCP) [16], and the National Comprehensive Cancer Network (NCCN), recommend LMWH-based therapy over warfarin-based therapy as the preferred VTE treatment in cancer patients,both for initial therapy and for long-term (6–12 months) management [17]. However, in Japan, LMWHs are not used for such treatment, and the oral direct factor Xa inhibitors (Xa inhibitors), edoxaban, rivaroxaban, and apixaban, have been approved for the treatment of VTE. These Xa inhibitors, which do not require laboratory monitoring or dose adjustment, have been shown in trials to be as effective as and probably safer than conventional anticoagulation (unfractionated heparin or LMWHs, followed by warfarin) for the treatment of VTE [18], [19], [20], [21]. Their fixed-dose regimens and oral administration make Xa inhibitors clinically attractive drugs for the treatment of VTE in patients with cancer. However, the proportion of patients with cancer in previous trials was small [8]. In addition, no clinical trial has compared the use of LMWHs versus Xa inhibitors in cancer patients. Therefore, their effectiveness and safety in cancer patients have not been fully elucidated. Among these drugs, edoxaban was first approved for VTE treatment in September 2014 in Japan. In the present study, we examined whether the efficacy and safety of edoxaban for the treatment of VTE differs between patients with and without cancer.