Structure-Activity Relationships of LMWHs

描述（由申请人提供）：肝素（UFH）和低分子量肝素（LMWH）是用于多种临床适应症的抗凝血剂和抗血栓形成剂。LMWH是使用各种化学和生物化学技术从UFH衍生的。因此，LMWH的精细化学结构在其分子组成、端基的化学差异和不同寡糖链的分布方面存在差异。虽然FDA已批准几种LMWH作为临床抗凝剂/抗血栓形成剂，但它们的活性和药理学特征差异显著。因此，在确定给定适应症的最佳剂量以及互换使用这些药物以实现最佳治疗结果方面都具有挑战性。虽然LMWH之间的总体结构差异通常归因于其活性和药代动力学性质的差异，但仍不清楚特定结构性质如何与不同LMWH的功能相关。 肝素抗凝活性的分子基础表明，肝素中低丰度（6- 8mol%）的特定五糖基序以高亲和力与抗凝血酶III（AT III）结合，并激活AT-III以主要抑制因子Xa和因子IIa（凝血酶）。由于每种LMWH都是通过UFH的随机（和不同的化学或酶）裂解得到的，因此AT-III结合五糖的定量丰度和构成LMWH的不同寡糖链中该基序的链长分布和位置存在差异。也许LMWH的关键功能（临床）属性是抗Xa/抗IIa比率和这些活性的药代动力学/动力学特征（即，的清除）。在这项研究中，我们建议利用我们开发的分析工具来确定控制AT-III结合五糖基序的丰度和位置的结构参数，并将这些结构参数与LMWH的两种主要活性即抗Xa和抗IIa及其体内消除的药代动力学相关联

DESCRIPTION (provided by applicant): Heparins (UFHs) and low molecular weight heparins (LMWHs) are blockbuster drugs used in several clinical indications as anticoagulants and antithrombotics. LMWHs are derived from UFH using a variety of chemical and biochemical techniques. As a result there are differences in the fine chemical structures of LMWHs in terms of their molecular composition, chemical differences in the end groups and distribution of different oligosaccharide chains. While several LMWHs have been approved by FDA as clinical anticoagulants/antithrombotics, they vary significantly in their activity and pharmacological profile. As a consequence, it has been challenging both in terms of determining optimal dosing for a given indication as well as using these drugs interchangeably to achieve the best therapeutic outcome. While the overall structural differences between LMWHs have been generally attributed to the differences in their activity and pharmacokinetic properties, it is still unclear how specific structural properties correlate with the function of different LMWHs. The molecular basis of heparin' s anticoagulant activity has shown that a specific pentasaccharide motif found in low abundance (6-8 mol percent) in heparin binds with high affinity to antithrombin III (AT III) and activates AT-III to primarily inhibit factor Xa and factor IIa (thrombin). Since each LMWH is derived through random (and distinct chemical or enzymatic) cleavage of UFH, there are differences in the quantitative abundance of the AT-III binding pentasaccharide and the chain length distribution and location of this motif in the different oligosaccharide chains that make up the LMWH. Perhaps the key functional (clinical) attribute of LMWHs is the anti-Xa/anti-IIa ratio and the pharmacokinetic/dynamic features of these activities (i.e., their clearance). In this study, we propose to utilize analytical tools that we had developed to determine the structural parameters that govern the abundance and location of the AT-III binding pentasaccharide motif and to correlate these structural parameters to the two primary activities of LMWHs viz. anti-Xa and anti-IIa and their pharmacokinetic in vivo elimination