Structure-Activity Relationships of LMWHs

描述（由申请人提供）：肝素（UFHs）和低分子量肝素（LMWHs）是一些临床适应症中用作抗凝血剂和抗血栓剂的重磅药物。低分子量水分子是利用多种化学和生化技术从UFH中提取出来的。因此，在分子组成、末端基团的化学差异以及不同低聚糖链的分布等方面，低分子量低聚糖的精细化学结构存在差异。虽然一些低分子肝素已被FDA批准作为临床抗凝血/抗血栓药，但它们的活性和药理学特征差异很大。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效果方面一直具有挑战性。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，但目前尚不清楚具体的结构特性如何与不同低分子肝素的功能相关联。

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