Stabilized Prasugrel enantiomers for pediatric sickle cell disease

用于儿童镰状细胞病的稳定普拉格雷对映体

基本信息

批准号：
9048538
负责人：
Sheila DeWitt
金额：
$ 29.45万
依托单位：
DEUTERX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-02 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9048538
关键词：
Accounting Adult Adverse effects Affect African American Animals Applications Grants Binding Biological Birth Bleeding time procedure Blood Platelets Blood Screening Blood Vessels Boxing Brain hemorrhage Characteristics Child Childhood Clinical Trials Cytochrome P450 Deuterium Development Disease Dose Drug Kinetics Enzyme Activation Erythrocytes Event Exhibits Exposure to Genes Goals Half-Life Hemoglobin Hemorrhage Hour Human body Hydrogen Hypoxia Image Individual Inherited Knockout Mice Lead Link Methods Modeling Mus Mutation Newborn Infant Organ Pain Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Platelet Activation Platelet Aggregation Inhibition Platelet Aggregation Inhibitors Platelet aggregation Preparation Resistance Risk Shapes Sickle Cell Anemia Testing Therapeutic Thrombus Time Tissues Wild Type Mouse acute coronary syndrome carcinogenesis clopidogrel drug candidate enantiomer ferric chloride genotoxicity hydroxyurea in vivo inhibitor/antagonist mouse model novel strategies pediatric patients pre-clinical public health relevance racemization receptor scale up sickling

项目摘要

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.

描述（由申请人提供）：镰状细胞病 (SCD) 是一种严重的遗传性疾病，在美国大约每 2,500 名新生儿中就有 1 人患有镰状细胞病，这一比例高于通过新生儿血液筛查检测到的任何其他疾病。只有一种治疗方法——羟基脲——可以被治愈。由于担心可能的遗传毒性和致癌作用，羟基脲未获批准用于治疗成人患者的 SCD 并发症。目前正在进行三项儿童 SCD 候选药物的临床试验。唯一进入第三阶段的治疗方法是普拉格雷，它是 Efient(r) 中的活性成分，被批准用于治疗急性疾病。普拉格雷对 ACS 和 SCD 患者的主要担忧是出血风险增加的黑框警告，这是出血性中风风险增加的儿科 SCD 儿童患者的一个重要问题。普拉格雷与其代谢物与 P2Y12 受体不可逆结合有关，导致血小板聚集减少，普拉格雷是两种镜像化合物的种族混合物。（对映体）在体内自发地相互转化，因此，将患者暴露于一种对映体及其相应的代谢物是不可能的，四种主要代谢物的 P2Y12 相对活性变化 16-190xs，而普拉格雷引起的一些出血是由于。 - P2Y12 的靶向效应，最近在 P2Y12 敲除小鼠模型中证明，出血风险增加可能主要是由于脱靶效应。我们的目标是开发一种稳定的普拉格雷单一对映体，用于治疗儿科 SCD，并显着降低出血风险。我们发现了一种通过用氘取代手性中心的氢来稳定快速相互转化的外消旋药物的单个对映体的方法。通过在普拉格雷中添加氘，我们将外消旋半衰期从“瞬时”减慢至 2.2 小时。在本次拨款申请中，我们将评估是否脱靶。普拉格雷的作用（如 P2Y12 敲除小鼠出血增加所定义）存在于普拉格雷单一对映体衍生的效力较低的 P2Y12 代谢物中。我们还将在离体血小板激活模型中评估血小板的靶向功效，以确认。来自另一种对映体的两种代谢物解释了全部或大部分所需的血小板聚集活性，这些结果将使我们能够开发出单一对映体。氘化普拉格雷用于儿科 SCD 的临床前开发。