Structure-Activity Relationships of LMWHs

说明(申请人提供)：肝素(UFHs)和低分子肝素(LMWHs)是在几个临床适应症中作为抗凝剂和抗血栓药使用的重磅炸弹药物。低分子肝素是利用各种化学和生化技术从超临界氢化物中提取出来的。因此，低分子肝素的分子组成、端基的化学组成和不同低聚糖链的分布在精细化学结构上存在差异。虽然几种低分子肝素已被FDA批准为临床抗凝剂/抗血栓药，但它们的活性和药理特征差异很大。因此，在确定给定适应症的最佳剂量以及交替使用这些药物以达到最佳治疗结果方面一直是具有挑战性的。虽然低分子肝素之间的总体结构差异通常归因于它们的活性和药代动力学性质的差异，但具体的结构性质如何与不同的低分子肝素的功能相关仍不清楚。 肝素S抗凝血活性的分子基础研究表明，肝素中低丰度(6-8mol%)的五糖基序与抗凝血酶III(AT III)高亲和力结合，并激活AT-III，主要抑制Xa因子和IIa因子(凝血酶)。由于每个LMWH都是通过UFH的随机(和不同的化学或酶)切割而产生的，因此AT-III结合的五糖的数量丰度以及该基序在组成LMWH的不同寡糖链中的链长分布和位置存在差异。可能低分子肝素的关键功能(临床)属性是抗Xa/抗IIa的比率和这些活动的药代动力学/动力学特征(即它们的清除性)。在本研究中，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LMWHs的两个主要活性关联起来。抗Xa和抗IIa及其体内消除的药代动力学

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