Improved Oral P-selectin Blocker for Prophylactic Sickle Cell Disease Therapy

描述（由申请人提供）：镰状细胞病（SCD）是一种治疗不善的衰弱性疾病，我们正在开发一种有前景的新型口服预防疗法。我们的药物存在着迫切的需求，因为全世界有数百万患有遗传性SCD的患者，在美国约有10万人，继续遭受着间歇性疼痛、残疾和过早死亡的折磨。羟基脲治疗有明显的缺陷，许多正在开发的药物靶向治疗而不是预防急性事件。大多数SCD发病的原因是血流量异常，特别是微血管流动停止引起的急性疼痛危象。血流缺陷是由多种病理生理引起的，包括一些独立于脱氧->镰状血红蛋白聚合->红细胞镰状反应的典型序列。基于内皮细胞p -选择素是持续损伤和急性血流停止的核心证据，我们将这种粘附分子作为我们的治疗目标。体外和初步临床数据显示，戊聚糖聚硫酸钠（PPS）可改善SCD患者微血管血流。然而，由于其有限的口服生物利用度和作用时间有限，市售PPS不是理想的治疗方法。因此，我们设计了两个协同计划来开发改进的第二代PPS-2，它将提供更高的口服生物利用度，使所有患者都能接受治疗量的PPS，并延长吸收时间，从而减少PPS给药的频率，提高患者的依从性。一项计划直接制订父计划；另一种方法采用PPS的分馏，鉴定药用上优越的PPS馏分，并配制最佳馏分。本建议侧重于分馏策略。较低分子量的PPS组分具有较好的口服生物利用度和较低的抗凝血活性。我们首先将测试不同分子量的PPS组分，以确定具有强大p选择素阻断活性的两个最低分子量组分

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a poorly treated debilitating condition for which we are developing a promising, new oral prophylactic therapy. A dire need exists for our drug, as millions of patients who have inherited SCD world-wide, ~100,000 in the US, continue to suffer with episodic pain, disability, and premature death. Hydroxyurea treatment has clear-cut deficiencies, and many drugs under development target treatment rather than prevention of acute events. The cause of most SCD morbidity is abnormal blood flow, notably acute pain crises that result from stoppage of microvascular flow. Defective blood flow results from multiple pathophysiologies, includin several that are independent of the paradigmatic sequence of deoxygenation -> sickle hemoglobin polymerization -> red cell sickling. Based on evidence that endothelial P-selectin is central to ongoing impairment and acute stoppage of flow, we are targeting this adhesion molecule with our therapy. In vitro and preliminary clinical data show that pentosan polysulfate sodium (PPS) improves microvascular blood flow in SCD. However, commercially available PPS is not ideal therapy because of its marginal oral bioavailability and limited duration of action. Accordingly, we have devised two synergetic plans to develop improved second generation PPS-2 that will provide increased oral bioavailability so all patients will receive therapeutic amounts of PPS and prolonged absorption so that the frequency of PPS administration will be reduced and patient compliance enhanced. One plan employs direct formulation of parent PPS; the other employs fractionation of PPS, identification of pharmaceutically superior PPS fractions, and formulation of the optimal fraction. This proposal focuses on the fractionation strategy. Lower molecular weight PPS fractions have better oral bioavailability and less anticoagulant activity than unfractionated PPS. We first will test PPS fractions of different molecular weighs to identify the two lowest molecular weight fractions that have robust P-selectin blocking activity and safe anticoagulant activity. Then we will test those two for oral bioavailability and pharmacokinetics in monkeys, the best nonhuman model of human bioavailability and pharmacokinetics. These studies will use high doses of radiolabeled PPS compounds to obtain the best bioavailability/pharmacokinetic data for PPS to date and first such dat for PPS fractions. These studies will identify the most favorable PPS fraction to be formulated and developed as PPS-2 and will enable filing a composition of matter patent. Our overarching goal is to improve the quality of life of SCD patients by bringing to market an effective oral P-selectin blocking drug for long-term administration to prevent sickle red blood cell sticking to the lining of blood vessels, improve blood flw, and avert acute painful episodes. This Phase I SBIR will provide a superior PPS fraction for PPS-2 formulation and development. Subsequent fractionation, formulation, preclinical testing in vitro and in sickle cell mice, GMP production, and IND filing ill be achieved with support of a Phase II SBIR grant.