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    • Because LTs are proved to mediate multiple biological and

    2022-11-29

    Because LTs are proved to mediate multiple biological and pathological responses in various disease states, the 5-LO biosynthetic pathway producing LTs from AA have been the target of drug discovery efforts for over two decades. As observed from literature, a pile of research efforts has been directed towards numerous targets in the pathway to develop antagonists of LTB4 and the cys-LT receptors, inhibitors of 5-LO and LTA4H as well as inhibitors of FLAP [96], [97], [98]. It is clear from the published reports, much of the early drug discovery efforts in the LT area was directed towards the treatment of allergy and (Z)-4-Hydroxytamoxifen [38], [99]. However, years of effort in these therapeutic areas have only yielded a few marketed products for the treatment of asthma including a direct 5-LO inhibitor, zileuton, and cys-LT1 receptor antagonists such as montelukast, pranlukast and zafirlukast [44], [100]. The therapeutic fate of 5-LO inhibitor zileuton was not very successful due to insufficient pharmacokinetics and significant hepatotoxicity risk which required constant monitoring of liver functions [3], [101], [102]. However, clinical application of cys-LT1 receptor antagonists was quite a success with wide prescription rate to asthma patients because of their excellent efficacy, safety and once-daily dosing regimen [103], [104]. However, the only shortage with this therapeutic class was the single blockage of LTD4's action on cys-LT1 receptor without disturbing the pathophysiological actions of LTB4 and other cys-LTs. Meantime, FLAP inhibitors such as GSK2190915/AM803, BAY-X-1005, ABT-080, MK-886 and MK-591 were evaluated in human clinical trials for asthma and found to be effective [4]. Among these initial candidates, MK-591 and BAY-X-1005 showed efficacy in phase II trials for asthmatic patients [46], [105], [106], but the development of ABT-080 was discontinued after a phase I study. Moreover, MK-591 did not demonstrate sufficient improvement in clinical studies to the standard therapy, and also produced mild skin rashes as unfavorable side effects. The most recent FLAP inhibitor advanced into phase II clinical trials in asthmatics is GSK-2190,915 (formerly known as AM-803), which is found efficacious on allergen-induced asthmatic response, and demonstrated good safety profile [107]. However, none of these compounds have yet reached to drug approval phase for the therapy of asthma patients. Much recent results from pharmacological and clinical studies have implicated LTs in CVD pathogenesis such as atherosclerosis as well as myocardial infarction (MI) and stroke [108], [109]. Scientific findings demonstrating the upregulated expression of 5-LO/FLAP proteins in human atherosclerotic lesions strongly associated this pathway with the pathophysiology of atherogenesis [110], [111]. Moreover, the selective inhibition of FLAP activity has been linked to a decrease in atherosclerotic lesion size in relevant animal experiments. For example, it was demonstrated for the first time that a FLAP inhibitor MK-886 reduced the development of atherosclerosis by decreasing plaque coverage in aortas of apoE/LDLR double knockout mice fed a high-fat diet [112]. In a subsequent study, four weeks administration of MK-886 to ApoE(−/−) CD4dnTGFbetaRII transgenic mice with aggravated atherosclerosis caused a significant reduction in atherosclerotic lesion size and T-cell content pointing out the importance of 5-LO/FLAP pathway in the modulation of T-cell-steered inflammatory responses in atherosclerosis [113]. These provocative results with MK-886 were also confirmed with another FLAP inhibitor BAY-X-1005, which also attenuated atherogenesis in ApoE/LDLR double knockout mice model [114]. Additional observations during examination of human atherosclerotic lesions also indicated the upregulated expression of FLAP, 5-LO and LTA4H, which were subsequently correlated with the plaque instability [115]. Furthermore, the FLAP gene has been linked by various genetic studies to CVDs including atherosclerosis, coronary artery disease, MI and stroke [116], [117], [118], [119], [120], [121], [122], [123]. Along with the earlier studies in atherosclerotic animal models, these genetic studies perfectly justified the important role of LTs in CV disorders. As a result, the Bayer compound BAY-X-1005 was licensed to deCODE genetics (named as DG-031), and was successfully evaluated in phase II study for reducing the biomarkers associated with MI, although participant recruitment in phase III was suspended due to unexpected formulation issues [124]. In a separate phase II trial with a second generation 5-LO inhibitor (VIA2291/ABT761), a reduction of coronary plaque volumes following an acute coronary syndrome was also demonstrated, once again implicating the benefits of intervening with LT pathway in CVD [125], [126].