因子Xa选择性抑制剂戊聚糖钠

因子Xa选择性抑制剂戊聚糖钠是新一代抗栓药物，对抗凝血酶Ⅲ有选择性高亲和力，特异性催化因子Xa失活，产生无因子Ⅱa抑制或抗血小板活性的抗凝血酶作用，从而显著降低静脉血栓栓塞的危险性。在预防大型矫形手术后静脉血栓栓塞时，戊聚糖钠皮下用药最佳剂量为1．5-3mg，每日一次给药，具有较好的时受性，在推荐临床剂量2．5mg时，与标准药物依诺肝素一样具有类似的时受性，但戊聚糖钠不会产生抗体诱导血小板减少的副作用。     

Xa因子抑制剂的药效团模型初探

Xa因子是一种丝氨酸蛋白酶，在凝血过程中起关键作用。有关研究显示，Xa因子可以成为一个抗凝作用的新靶点，在口服抗凝血药的开发中扮演着重要角色。本文综述了近年来Xa因子抑制剂抗血凝作用的研究进展并对其药效团模型进行了探索。     

直接Xa因子抑制剂贝曲沙班

心脑血管疾病已成为全球致病和致死率最高的疾病之一,血栓形成是心脑血管疾病的主要诱因。传统的抗凝药物以肝素和华法林为主,但存在出血、血小板减少的明显不良反应。Xa因子处于内源性凝血和外源性凝血通路的中心位置,并且每分子的Xa因子可活化产生约1 000分子的凝血酶,Xa因子抑制剂的出现为抗凝药物的发展提供了新的方向。贝曲沙班是一种口服的直接Xa因子抑制剂,也是目前唯一经肾脏排泄最少的药物,在一系列研究中显示出良好的治疗前景。主要从贝曲沙班的药物概况、相关背景、合成路线、作用机制、临床研究等方面进行介绍。     

开发中的新型口服抗凝血药－Xa因子抑制剂

血管内血栓的形成是心肌梗塞、不稳定心绞痛及肺栓塞等疾病发生的关键性因素,抗凝药则是阻止血液凝固的一类药物.Xa因子抑制剂作为新型的抗凝血药,近年来受到了广泛的关注.Rivaroxaban的上市及处于临床研究中的Apixaban、Eribaxaban、Betrixaban、LY 517717、DU-176b、YM 150及TAK442等诸多口服Xa因子抑制剂的出现,为血栓栓塞疾病患者带来了新的福音.本文从Xa因子抑制剂与凝血因子Xa结合的晶体结构以及各Xa因子抑制剂的临床特点入手,来综述近年来开发的或正在开发中的Xa因子抑制剂.     

微生物来源的Xa因子抑制剂F02-2172的研究

利用一种由本中心建立的Xa因子抑制剂高通量体外筛选模型，从大量真菌菌库及其来源的代谢产物中筛选到了一株可产生阳性活性化合物的菌株F02ZA-2172，该菌株的发酵液经有机溶剂提取、硅胶柱色谱、ODS柱色谱、Sephadex LH-20柱色谱及HPLC制备分离，得到F02-2172A、B和C三个活性化合物。经紫外、质谱、核磁等理化数据分析，确定这三个化合物分别与已知化合物6-epi-ophiobolinK、ophiobolin K和ophiobolin G的结构相同，但该类化合物对Xa因子的抑制活性至今未见报道。     

口服Xa因子直接抑制剂阿哌沙班的临床研究进展

阿哌沙班是口服Xa因子直接抑制剂,继达比加群酯和利伐沙班后上市,用于择期髋关节或膝关节置换手术的成年患者,以预防静脉血栓形成。本文主要介绍这个新药的研发背景、作用机制、药动学和临床试验。     

沙班类凝血因子Xa抑制剂的研究进展

血栓形成是导致心脑血管疾病的重要诱因,而抗凝治疗在预防血栓栓塞性疾病中起着很重要的作用。凝血因子Xa(FXa)是研究新型抗凝血药的一个重要的靶点,其中,沙班类抗凝血药是最经典的FXa抑制剂,近年来发展迅速,沙班类抗凝血药物具有口服方便、疗效和安全性好,受食物和其他药物影响小及无需监测国际标准化比值(INR)等优点,在临床上广泛应用并弥补了传统抗凝血药的不足。本文对沙班类凝血因子Xa抑制剂的研究进展进行综述。     

CDK5抑制剂研究进展

细胞周期蛋白依赖性激酶-5（cyclin—dependent kinase-5,CDK5）是一个多功能的丝氨酸／苏氨酸蛋白激酶,它不参与细胞周期调控,其生理功能主要表现在维持神经细胞的正常发育和有丝分裂后神经细胞的功能及骨架结构。CDK5抑制剂研究备受关注,对治疗神经退化性疾病、糖尿病、癌症和疼痛具有潜在的疗效。本文对已报道的CDK5抑制剂的结构、与蛋白的作用模式和构效关系进行综述,为合理地设计该类药物提供有益的启示。     

凝血Xa因子直接抑制剂的研究进展与临床应用评价

目的：抗凝治疗是心房颤动药物治疗的核心,但鉴于目前临床应用的传统抗凝血药存在的局限性,一类起效快速、选择性高、作用直接抑制凝血Xa因子的药物应运而生,为临床抗凝治疗提供了更多的选择。本文总结凝血Xa因子直接抑制剂的研究进展与临床评价。方法：采用国内、外文献分析方法。结果与结论：相对于华法林而言,凝血Xa因子直接抑制荆可更特异地抑制血栓形成,抗凝作用起效快,无需监测凝血指标和调整剂量,所致出血风险低,使抗凝作用由多靶点向单靶点迈进,成为临床一线重要的抗凝血药。     

Recent advances in the discovery and development of direct coagulation factor Xa inhibitors

Coronary heart disease (CHD) is the leading cause of mortality and morbidity in the United States. Currently, there are approximately 12 million Americans with CHD, which is most frequently caused by atherosclerosis. The thrombotic complications of atherosclerosis, such as acute coronary syndrome and ischemic stroke, can be fatal and those who survive such events have a far greater risk of future cardiovascular events. This huge medical need cries out for improved novel anticoagulants, antiplatelet agents, and profibrinolytic agents. These agents will successfully respond to the medical need by providing safe, effective, and easily administered treatments that have little, if any, drug and food interactions and that require minimal monitoring. The currently approved antiplatelet agent, clopidogrel, has satisfied some of these requirements and has played a large role in expanding the antithrombotic market over the past few years. New antithrombotics approaching the marketplace, such as the prodrug thrombin inhibitor ximelagatran, have promise in expanding the antithrombotic market further. Over the past two decades, the pharmaceutical industry has mounted a huge effort to develop antithrombotics that function by inhibiting key enzymes positioned at "higher" levels of the coagulation system. Direct inhibitors of factor Xa, which may provide a better safety and efficacy profile than currently available agents, appear to be the next major class of antithrombotic agents poised to take the pharmaceutical industry one step closer to delivering the ideal antithrombotic agent. This review focuses on recent innovations in the discovery and development of potent parenteral and oral direct factor Xa inhibitors.     

Recent advances in Factor Xa inhibitors

Due to its critical role in the coagulation cascade Factor Xa became an important target for antithrombotic drug development. The design of the first generation of Factor Xa inhibitors was based on dibasic inhibitors binding to both the primary specificity pocket of Factor Xa and a putative cation binding site. The high basicity of these compounds limited the oral bioavailability and thus prohibited convenient oral administration in a therapeutic setting. Hence, recent efforts have focused on the development of non-peptide inhibitors of low basicity by screening and rational design. This report provides an overview of the recent patent literature from 1998 to 2000.     

Recent advances in the discovery of tissue factor/factor VIIa inhibitors and dual inhibitors of factor VIIa/factor Xa

The search for an ideal anticoagulant has spanned decades and has taken several approaches to the identification of novel target molecules for preventing and treating thrombosis. In the group of anticoagulants acting through direct inhibition of coagulation factors, most research has focused on thrombin and factor Xa inhibitors. Attention has been drawn most recently to factor VIIa as a promising anticoagulation target, because of its role in complex with tissue factor, in initiating the coagulation cascade following blood vessel damage. Several reports suggest that inhibitors of the tissue factor/factor VIIa complex prevent thrombosis with a lower bleeding risk than other types of inhibitors. Accordingly, there is increasing interest in the generation of potent and selective small-molecule factor VIIa inhibitors that can be safely administered once or twice daily in an oral formulation with no need for routine coagulation monitoring. The emphasis of this review will be placed on recent advances in the development of the small-molecule inhibitors of factor VIIa complexed with tissue factor. The role of factor VIIa and tissue factor as initiators of the coagulation cascade following blood vessel damage is described, along with the structure of the active site of factor VIIa.     

Recent advances in clinical trials of the direct and indirect selective Factor Xa inhibitors

Over the years, pharmacological intervention to prevent undesired intravascular coagulation and the associated detrimental effects has been a clinical challenge. The first generation of anticoagulant agents, warfarin and unfractionated heparin (UFH), involve indirect mechanisms of inhibiting the coagulation cascade. Fractionated, or low-molecular weight, heparins (LMWHs) are more selective for coagulation Factor Xa (FXa) over thrombin (FIIa). LMWHs also utilise an indirect mechanism of inhibition and have improved pharmacokinetic, pharmacodynamic and therapeutic profiles over UFH. The success of LMWHs, along with the pivotal location of FXa in the coagulation cascade, has prompted interest in the discovery and development of selective FXa inhibitors. There are two general classes of FXa inhibitors in development, of which SR90107A/ORG31540, an antithrombin-III-dependent pentasaccharide and DX-9065a, a small molecule direct FXa inhibitor, have published clinical data. SR90107A/ORG31540 and DX-9065a offer safe, predictable pharmacokinetic and pharmacodynamic profiles when administered subcutaneously and intravenously, respectively, to healthy volunteers and appear to be progressing through clinical development. The purpose of this review is to compile and summarise the published Phase I and II clinical data for SR90107A/ORG31540 and DX-9065a.     

Recent advances in clinical trials of the direct and indirect selective Factor Xa inhibitors

Over the years, pharmacological intervention to prevent undesired intravascular coagulation and the associated detrimental effects has been a clinical challenge. The first generation of anticoagulant agents, warfarin and unfractionated heparin (UFH), involve indirect mechanisms of inhibiting the coagulation cascade. Fractionated, or low-molecular weight, heparins (LMWHs) are more selective for coagulation Factor Xa (FXa) over thrombin (FIIa). LMWHs also utilise an indirect mechanism of inhibition and have improved pharmacokinetic, pharmacodynamic and therapeutic profiles over UFH. The success of LMWHs, along with the pivotal location of FXa in the coagulation cascade, has prompted interest in the discovery and development of selective FXa inhibitors. There are two general classes of FXa inhibitors in development, of which SR90107A/ORG31540, an antithrombin-III-dependent pentasaccharide and DX-9065a, a small molecule direct FXa inhibitor, have published clinical data. SR90107A/ORG31540 and DX-9065a offer safe, predictable pharmacokinetic and pharmacodynamic profiles when administered subcutaneously and intravenously, respectively, to healthy volunteers and appear to be progressing through clinical development. The purpose of this review is to compile and summarise the published Phase I and II clinical data for SR90107A/ORG31540 and DX-9065a.     

Recent advances in the development of immunostimulatory oligonucleotides

Some immune cells recognize distinct molecular structures present in pathogens through specific pattern recognition receptors that are able to distinguish prokaryotic DNA from vertebrate DNA. The detection of invading microbial DNA is based on the recognition of unmethylated deoxycytidyl-deoxyguanosin dinucleotide (CpG) motifs. Synthetic oligonucleotides (ODNs) containing these CpG motifs are able to activate both innate and acquired immune responses through a signaling pathway involving Toll-like receptor 9 (TLR9). Depending on the sequence, length, as well as number and positions of CpG motifs in an ODN, distinct immunostimulatory profiles can be observed. These immunostimulatory profiles can be further modified and fine-tuned by appropriate chemical modifications, leading to preclinical and clinical development of CpG ODNs in cancer, allergy, asthma and infectious diseases.     

Recent advances in the development of multi-kinase inhibitors

During the last two decades, protein kinases have emerged as a major target for cancer therapy and a large number of selective kinase inhibitors have been developed as potential anticancer drugs. To avoid unpredictable toxic effects, researchers usually aim at designing highly selective inhibitors. But since the formation and progression of a tumor has to be considered as a multifactorial process, which is dependent on different signalling pathways, it seems reasonable to establish anticancer therapies that target several kinases associated with tumor growth. In general, this can be achieved by two different strategies, either by concomitantly using a combination of a set of selective kinase inhibitors or by administering a single agent, which simultaneously inhibits several kinases, a so called multi-kinase inhibitor. In this review, benefits and obstacles of both strategies are discussed. An overview over recently approved and newly upcoming multi-kinase inhibitors is given.     

Recent advances in the development of gamma-secretase inhibitors

Alzheimer's disease is a neurodegenerative disorder that exerts a huge psychological and social toll in modern societies. The current hypothesis for the cause of this illness is that it is the result of aberrant production of beta-amyloid (A beta) and plaque deposition in the brain of affected individuals. New therapeutic interventions seek to stop or even reverse the course of the disease by inhibiting this aggregation or reducing A beta formation. The use of inhibitors of gamma-secretase, a key enzyme in the production of A beta, is currently undergoing preclinical and clinical evaluation. Small molecule inhibitors which demonstrate efficacy in reducing A beta burden in mice have thus been recently discovered. This review summarizes the development of such inhibitors in light of our current understanding of the function of gamma-secretase. It also provides an evaluation of the therapeutic potential for this class of compounds with the recent discovery of other biochemical pathways associated with gamma-secretase, such as Notch signaling.     

Recent advances in the development of therapeutic peptides

Peptides have unique characteristics that make them highly desirable as therapeutic agents. The physicochemical and proteolytic stability profiles determine the therapeutic potential of peptides. Multiple strategies to enhance the therapeutic profile of peptides have emerged. They include chemical modifications, such as cyclization, substitution with d-amino acids, peptoid formation, N-methylation, and side-chain halogenation, and incorporation in delivery systems. There have been recent advances in approaches to discover peptides having these modifications to attain desirable therapeutic properties. We critically review these recent advancements in therapeutic peptide development.