Stabilized Prasugrel enantiomers for pediatric sickle cell disease

 描述(申请人提供)：镰状细胞病(SCD)是一种严重的遗传性疾病，在美国大约每2500名新生儿中就有一人发生，高于新生儿血液筛查发现的任何其他疾病。只有一种治疗方法，羟基脲，被批准用于治疗成年患者的SCD并发症。羟基脲不被批准用于儿童，因为担心可能的遗传毒性和致癌作用。目前有三项针对儿童SCD患者的候选药物的临床试验正在进行中。唯一进展到第三阶段的治疗方法是普拉格雷，它是Effient(R)中的有效成分，被批准用于急性 冠状动脉综合征(ACS)。普拉格雷对ACS和SCD患者的主要担忧是增加出血风险的黑匣子警告。这在出血性卒中风险增加的儿童SCD儿科患者中是一个重要的问题。普拉格雷的有益作用与其代谢产物与P2Y12受体的不可逆结合有关，从而导致血小板聚集减少。普拉格雷是两种镜像化合物(对映体)的外消旋混合物，在体内自发地相互转换。因此，患者只接触一种对映体及其相应的代谢物是不可能的。四种主要代谢产物的P2Y12相对活性变化在16-190xs之间。虽然普拉格雷引起的一些出血是由于P2Y12的靶向效应，但最近在P2Y12基因敲除小鼠模型中证明，出血风险的增加很可能主要是由于靶外效应。我们的目标是开发一种稳定的、单一的普拉格雷对映体，用于治疗儿童SCD，并显著降低出血风险。我们发现了一种稳定快速相互转化外消旋药物的单个对映体的方法，方法是用氢取代手性中心的氢。通过在普拉格雷中加入氢元素，我们已经将消旋半衰期从“瞬时”减慢到2.2小时。在这项赠款申请中，我们将评估普拉格雷的非靶标效应，如在P2Y12基因敲除小鼠中增加出血所定义的，是否存在于来自单一普拉格雷对映体的较低效力的P2Y12代谢物中。我们还将在体外血小板激活模型中评估血小板的靶向疗效，以确认来自另一对映体的两种代谢物能够解释所有或大部分所需的血小板聚集活性。这些结果将使我们将单一的氢化普拉格雷对映体推进到儿童SCD的临床前开发。

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a severe inherited disease that occurs in about 1 in 2,500 newborns in the U.S, greater than that of any other condition detected by newborn blood screening. Only one treatment, hydroxyurea, is approved for the complications of SCD in adult patients. Hydroxyurea is not approved in children due to concerns regarding possible genotoxicity and carcinogenesis. There are currently three ongoing clinical trials with drug candidates for pediatric SCD patients. The only treatment that has progressed to Phase 3 is prasugrel, the active ingredient in Effient(r) which is approved for acute coronary syndrome (ACS). The major concern of prasugrel for ACS and SCD patients is the black box warning for increased risk of bleeding. This is a significant concern in pediatric SCD pediatric patients who have increased risk of hemorrhagic stroke. The beneficial effects of prasugrel have been linked to the irreversible binding of its metabolites to P2Y12 receptors that leads to reduced aggregation of platelets. Prasugrel is a racemic mixture of two mirror image compounds (enantiomers) that spontaneously interconvert in vivo. As such, exposing patients to just one enantiomer and its corresponding metabolites is impossible. The P2Y12 relative activity of the four major metabolites varies 16-190xs. While some bleeding caused by prasugrel is due to the on-target effect of P2Y12, it has recently been demonstrated in a P2Y12 knockout mouse model that the increased bleeding risk is likely due largely to off-target effects. Our aim is to develop a stabilized, single enantiomer of prasugrel for the treatment of pediatric SCD with dramatically reduced risk of bleeding. We discovered a method to stabilize the individual enantiomers of rapidly interconverting racemic drugs by replacing the hydrogen at the chiral center with deuterium. By adding deuterium to prasugrel, we have slowed the racemization half-life from "instantaneous" to 2.2 hours. Within this grant application we will assess whether the off-target effects of prasugrel, as defined by increased bleeding in the P2Y12 knockout mice, resides in the less potent P2Y12 metabolites derived from a single enantiomer of prasugrel. We will also assess the on-target efficacy with platelets in an ex vivo platelet activation model to confirm that the two metabolites derived from the other enantiomer account for all or most of the desired platelet aggregation activity. These results will allow us advance a single enantiomer of deuterated prasugrel to preclinical development for pediatric SCD.