Bifunctional potassium-ATP channel opener and redox catalyst for therapy of spina

用于脊柱治疗的双功能钾-ATP 通道开放剂和氧化还原催化剂

• 批准号: 8769880
• 负责人: PRAKASH G JAGTAP
• 金额: $ 23.15万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769880
• 关键词: A Mouse; Acetylcysteine; Action Potentials; Acute; Adult; Adverse effects; Animal Model; Animals; Antioxidants; Arrhythmia; Ascorbic Acid; Blinded; Cardiac; Chemicals; Chemistry; Clinic; Clinical; Collaborations; Control Groups; Contusions; Development; Diazoxide; Disease; Dose; Drug Exposure; Drug Targeting; Exhibits; Female; Foundations; Heart; Hemorrhagic Shock; Histologic; Hydrogen Peroxide; Hydroxyl Radical; Hyperglycemia; Hypotension; Injury; Investigation; Ischemic Preconditioning; Kidney; Kinetics; Label; Laminectomy; Limb structure; Lung; Marketing; Measures; Medical; Mitochondria; Modeling; Motor; Mus; Neurological outcome; Ohio; Operative Surgical Procedures; Orphan Drugs; Outcome; Oxidation-Reduction; Pathogenesis; Pathologic; Pathway interactions; Penetration; Peroxonitrite; Pharmaceutical Preparations; Phase; Pilot Projects; Pinacidil; Placebo Control; Plasma; Poly(ADP-ribose) Polymerases; Potassium; Pre-Clinical Model; Prevention; Product R; Pyrrolidines; Randomized; Reaction; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Rodent; Rodent Model; Secondary to; Series; Small Business Innovation Research Grant; Solutions; Spin Trapping; Spinal; Spinal Cord; Spinal cord injury; Stress; Superoxides; Testing; Therapeutic; Therapeutic Agents; Tissues; Tocopherols; Toxic effect; Trauma; Universities; Ventricular Fibrillation; antioxidant therapy; attenuation; base; catalase; catalyst; clinical practice; clinically relevant; drinking water; functional outcomes; improved; indexing; innovation; mimetics; novel; pre-clinical; professor; prospective; public health relevance; pyrrolidine; response; small molecule

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a first-in-class cytoprotective small molecule (R-801) for the prevention of spinal cord injury (SCI) based upon the chemical fusion of 2 discrete chemical domains that: 1) target redox stress via a nitroxide spin-trap moiety, and 2) trigger the endogenous ischemic-preconditioning response via mitochondrial-selective K+-ATP channel activation. We have confirmed a powerful effect of R- 801 in rodent models of trauma, including hemorrhagic shock and ischemia reperfusion injury of the heart, lung, limb, and kidney. In a pilot study of spinal cord trauma (SCT), resuscitation of mice with R-801 produced an accelerating and non-plateauing improvement in motor function (20% total recovery over the first 10 days). R-801 has shown no evidence of toxicity in rodents and large animals. At present, R-801 is the first and only safe, effective, and selective mito-K+-ATP channel opener in development, as no other firm or academic center has succeeded to date in inventing a safe, effective, and selective mito-K+-ATP channel opener. We now propose to verify the pre-clinical feasibility of R-801 in a classic model of SCT and to deepen the understanding of its mechanism of action. Phase 1 SBIR Specific Aim: Establish the PD profile of R-801 in an experimental murine model of SCI. In order to test the hypothesis that R-801 effectively resuscitates SCT, RTX will carry out a pathologic and functional analysis in a prospective, randomized, single-blinded, placebo-controlled investigation in mice. In collaboration with Professor Philip Popovich (Ohio University), adult female CD1 mice will be subjected to SCT using a standardized model of contusion injury. Sham injury (laminectomy without SCT) and vehicle control groups will be compared to a group receiving R-801. The initial 2 doses of R-801 (80 mg/kg/dose), given 1 and 3 h after SCT, will be administered intraperitoneally (IP) in order to obtain a rapid tissue penetration of high levels of the drug int spinal cord tissue. Thereafter, R-801 will be provided in the drinking water (as a 0.2% solution) in order to optimize steady-state drug exposure. In Series A, mice (n=10 per group) will be sacrificed 48 h after SCT for histologic and immunohistochemical analysis of the spinal cord for evidence of of poly(ADP-ribose) polymerase activation and ONOO- formation. In Series B, open field locomotor function will be analyzed in adult female SCI mice (n=10 per group) for a period of 2 months post SCT. Mice will be acclimated to the open field ~1 week prior to SCT. Indices of functional recovery will be measured using the Open field-testing (Basso Mouse Scale; BMS) locomotor rating scale. BMS scores will then be obtained pre-injury and again at weekly intervals. Terminal plasma concentrations of R-801 will be obtained, in order to construct a PD profile relating the efficacy in each dose group to functional, morphologic, and immunohistochemical endpoints. Verification that R-801 resuscitation ameliorates morphologic and functional outcomes will provide a logical foundation for commercial development of parenteral R-801 as an emergent therapy for acute SCI.

描述（由申请人提供）：Radikal Therapeictics（RTX）正在开发一种基于2个离散化学结构域的化学融合，以预防脊髓损伤（SCI）的一流的细胞保护小分子（R-801），该分子基于2个离散化学结构域的化学融合：1：1）通过硝基氧化物旋转的iSCHIDICTICT，并通过硝基氧化物触发剂量触发剂量的反应，并且线粒体选择性K+-ATP通道激活。我们已经证实了R-801在啮齿动物创伤模型中的强大作用，包括心脏，肺，肢体和肾脏的出血性休克和缺血再灌注损伤。在一项针对脊髓创伤（SCT）的试点研究中，R-801的小鼠复​​苏产生了运动功能的加速和非平局改善（在前10天，总恢复为20％）。 R-801尚未显示出在啮齿动物和大动物中毒性的证据。目前，R-801是开发中的第一个也是唯一的安全，有效和选择性的MITO-K+-ATP频道开启器，因为没有其他公司或学术中心在发明安全，有效和选择性的MITO-K+-ATP频道开启器上都没有成功。现在，我们建议在经典的SCT模型中验证R-801的临床前可行性，并加深对其作用机理的理解。第1阶段SBIR特定目的：在SCI的实验鼠模型中建立R-801的PD谱。为了检验R-801有效恢复SCT的假设，RTX将在小鼠中的前瞻性，随机，单叶，安慰剂控制的研究中进行病理和功能分析。与菲利普·波波维奇（Philip Popovich）教授（俄亥俄州大学）合作，成年女性CD1小鼠将使用标准化的挫伤损伤模型进行SCT。将假损伤（无SCT椎板切除术）和媒介物对照组与接受R-801的组进行比较。在SCT后1和3小时给定的2剂R-801（80 mg/kg/剂量）将腹膜内（IP）给药，以便获得高水平的药物INT脊髓组织的快速组织渗透。此后，将在饮用水中提供R-801（作为0.2％的溶液），以优化稳态药物暴露。在A系列中，SCT后48 h处置小鼠（n = 10），以进行脊髓的组织学和免疫组织化学分析，以证明聚（ADP-核糖）聚合酶激活和ONOO形成的证据。在B系列中，将在SCT后2个月内在成年女性科学小鼠（每组n = 10）中分析开放式运动功能。小鼠将适应SCT前1周的开放场。功能恢复的指标将使用开放式测试（Basso小鼠量表； BMS）运动量表来衡量。然后，BMS分数将在受伤前获得，并在每周的间隔内再次获得。将获得R-801的末端血浆浓度，以构建将每个剂量组中的功效与功能，形态学和免疫组织化学终点的疗效有关的PD谱。 R-801复苏可以改善形态和功能结果的验证将为肠胃外R-801的商业发展提供逻辑基础，作为急性SCI的新兴治疗。