Pharmacological Validation of Vascular KATP Channels for Modulating Ductus Arteriosus Tone

调节动脉导管张力的血管 KATP 通道的药理学验证

• 批准号: 10053976
• 负责人: Jerod S. Denton
• 金额: $ 67.91万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053976
• 关键词: Acetaminophen; Alprostadil; Aorta; Arteries; Biological Assay; Biology; Birth; Blood; Blood Vessels; Blood flow; Cantu syndrome; Cardiovascular system; Catheters; Chemicals; Clinical; Closure by clamp; Collaborations; Congenital Heart Defects; Data; Defect; Development; Drug Kinetics; Drug Targeting; Duct (organ) structure; Ductus Arteriosus; Electrophysiology (science); Exhibits; Failure; Fluorescence; Gases; Genetic; Goals; Human; Ibuprofen; In Vitro; Indomethacin; Infant; Institutes; Lead; Left; Libraries; Life; Ligands; Ligation; Link; Lung; Mechanics; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myography; Neonatal; Neurologic; Newborn Infant; Operative Surgical Procedures; Organ; Patent Ductus Arteriosus; Pathway interactions; Patients; Perfusion; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiology; Placental Circulation; Play; Potassium; Potassium Channel; Preparation; Property; Prostaglandins; Pulmonary artery structure; Regulation; Reporting; Risk; Rodent; Role; Savings; Series; Shunt Device; Side; Smooth Muscle Myocytes; Structure; Technology; Thallium; Theft; Therapeutic; Time; Validation; analog; base; constriction; drug discovery; experimental study; fetal; gain of function mutation; high throughput screening; in utero; in vivo; inhibitor/antagonist; lead optimization; mouse model; new therapeutic target; novel; patch clamp; pup; response; small molecule; small molecule libraries; therapeutic target; tool; vascular bed; vasoconstriction

PROJECT SUMMARY The ductus arteriosus (DA) is an essential fetal artery connecting the aorta and pulmonary artery, which shunts blood away from the developing lungs in utero . Circulatory adaptation at birth requires rapid constriction of the DA to facilitate proper perfusion of the newly inflated lungs. Persistent patency of the neonatal DA (PDA) is a significant clinical problem that is inefficiently managed with currently available therapies. Pharmacology-based PDA therapeutics non-specifically target the prostaglandin pathway, have worrisome off target effects on other vascular beds, and are ineffective in approximately 30% of patients. While surgical ligation and catheter-based closure are effective alternatives, these mechanical approaches come with their own risks and limitations. Consequently, there is a significant need to identify and rigorously validate novel drug targets for manipulating DA tone. An emerging body of physiological and genetic data from our group and others has implicated vascular ATP-regulated potassium (KATP) channels as novel drug targets for regulating DA tone. Specifically, we show here for the first time that KATP channels comprised of pore-forming Kir6.1 and regulatory SUR2B subunits are highly enriched in smooth muscle cells of the PDA and regulate DA tone in response to pharmacological modulation. Unfortunately, the lack of specific Kir6.1/SUR2B inhibitors (and activators) has precluded a rigorous assessment of the therapeutic potential of DA KATP channels for treating PDA. In this multi-PI collaboration, which will benefit from complementary expertise in potassium channel drug discovery (Drs. Denton/Lindsley) and DA physiology and pharmacology (Dr. Shelton), we propose to employ high- throughput screening (HTS) and medicinal chemistry to develop an extensive “tool kit” of vascular-specific KATP channel modulators for validating Kir6.1/SUR2B channels for regulating DA tone in vitro and in vivo. In Aim 1, we will employ a fully validated HTS assay to interrogate ~110,000 small molecules for potent and selective Kir6.1/SUR2B modulators. In Aim 2, we will use medicinal chemistry to optimize lead compounds for selectivity and potency and determine compound metabolism and pharmacokinetic properties. In Aim 3, we will evaluate the efficacy of lead compounds to regulate mouse and human DA tone using isolated vessel myography assays and in vivo mouse models of PDA. The successful completion of these aims will generate critically needed tool compounds for modulating DA tone and validate Kir6.1/SUR2B channels as novel therapeutic targets for treating PDA.

项目概要 动脉导管（DA）是连接主动脉和肺动脉的重要胎儿动脉，它分流 血液远离子宫内正在发育的肺部 。 出生时的循环适应需要快速收缩 DA 促进新充气肺部的适当灌注。新生儿 DA (PDA) 的持续通畅是 目前可用的疗法无法有效解决的重大临床问题。基于药理学 PDA 疗法非特异性针对前列腺素途径，对其他途径具有令人担忧的脱靶效应 血管床，并且对大约 30% 的患者无效。虽然手术结扎和导管为基础 关闭是有效的替代方案，但这些机械方法有其自身的风险和局限性。 因此，非常需要识别和严格验证用于操纵的新药物靶点 DA 语气。我们小组和其他人的一系列新兴的生理和遗传数据表明 血管 ATP 调节钾 (KATP) 通道作为调节 DA 张力的新药物靶点。具体来说， 我们在这里首次展示 KATP 通道由成孔 Kir6.1 和调节性 SUR2B 组成 亚基在 PDA 的平滑肌细胞中高度富集，并调节 DA 音调以响应 药理调节。不幸的是，由于缺乏特定的 Kir6.1/SUR2B 抑制剂（和激活剂）， 妨碍了对 DA KATP 通道治疗 PDA 的治疗潜力进行严格评估。在这个 多 PI 合作，这将受益于钾通道药物发现方面的互补专业知识 （Drs. Denton/Lindsley）和 DA 生理学和药理学（Dr. Shelton），我们建议采用高 通量筛选 (HTS) 和药物化学，开发血管特异性 KATP 的广泛“工具包” 用于验证 Kir6.1/SUR2B 通道在体外和体内调节 DA 音调的通道调制器。在目标 1 中， 我们将采用经过充分验证的 HTS 测定来检测约 110,000 个小分子，以获得有效和选择性的结果 Kir6.1/SUR2B 调制器。在目标 2 中，我们将使用药物化学来优化先导化合物的选择性 和效力并确定化合物代谢和药代动力学特性。在目标 3 中，我们将评估 使用离体血管肌电图研究先导化合物调节小鼠和人类 DA 音调的功效 PDA 的测定和体内小鼠模型。这些目标的成功完成将产生至关重要的影响 调节 DA 音调和验证 Kir6.1/SUR2B 通道作为新型治疗药物所需的工具化合物 治疗 PDA 的目标。