Bifunctional Nitric Oxide Donor Refractory to Nitrate Tolerance

双功能一氧化氮供体难以耐受硝酸盐

• 批准号: 8248629
• 负责人: Garry John Southan
• 金额: $ 24.05万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248629
• 关键词: Address; Animal Model; Animals; Antihypertensive Agents; Aortic Aneurysm; Biochemical; Biological Assay; Blood Vessels; Canis familiaris; Cardiovascular system; Chemicals; Chromosome abnormality; Chronic; Clinical Trials; Conscious; Cyclic GMP; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Enzymes; Essential Hypertension; Event; Exposure to; Fossa; Human; Hydrogen Peroxide; Hypertension; In Vitro; Inbred SHR Rats; Intestines; Intravenous; Isosorbide Dinitrate; Isosorbide Mononitrate; Life; Liver; Measurement; Medical; Metabolic; Metabolism; Micronucleus Tests; Microsomes; Miniature Swine; Mitochondria; Modeling; Monitor; Monocrotaline; Newborn Infant; Nitrates; Nitric Oxide; Nitric Oxide Donors; Oral; Peripheral; Peroxonitrite; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Pilot Projects; Plasma; Pyrrolidines; Rattus; Reactive Oxygen Species; Refractory; Regimen; Relative (related person); Resolution; Rodent; Safety; Secondary to; Series; Small Business Innovation Research Grant; Stenosis; Stroke; Superoxide Dismutase; System; Tachyphylaxis; Technology; Texas; Therapeutic; Tissues; Toxicogenetics; Toxicokinetics; Toxicology; United States National Institutes of Health; Universities; Vasodilation; Vasodilator Agents; aldehyde dehydrogenases; base; blood pressure regulation; capsule; cardiovascular risk factor; catalase; catalyst; clinically relevant; design; hemodynamics; in vivo; inhaled nitric oxide; innovation; instrument; kidney vascular structure; man; mimetics; neurobehavioral; next generation; novel; pressure; professor; pulmonary arterial hypertension; pyrrolidine; respiratory; small molecule; telemetering; urinary

DESCRIPTION (provided by applicant): Nitrate therapy for peripheral hypertension (HTN) is limited in efficacy due to the rapid induction of tachyphylaxis, via its inactivation of mitochondrial aldehyde dehydrogenase. The introduction of a nitrate therapy free of tolerance induction would represent a significant commercial opportunity and address a major unmet medical need. Radikal Therapeutics (RTX) is developing R-100, a small molecule agent formed from the covalent linkage of: 1) an organic nitrovasodilator domain that releases nitric oxide (NO), and 2) a pyrrolidine nitroxide domain that acts as a catalyst of reactive oxygen species degradation: a superoxide dismutase (SOD) mimetic, a catalase mimic that detoxifies hydrogen peroxide, and a peroxynitrite decomposition catalyst. R-100 has been proven in ex vivo and in vivo rodent systems to act as a powerful vasodilator that does not induce tolerance. R-100 has not yet been evaluated for induction of nitrate tolerance in chronically-dosed conscious large animals, a critical milestone in its pharmaceutical development. Aim #1: Establish the pharmacodynamic (PD) profile of R-100 in a conscious, ambulatory, large-animal model of HTN A series of hemodynamic studies wil be conducted in conscious, instrumented, ambulatory, and telemetered minipigs with HTN secondary to an endovascular-created, unilateral, renovascular stenosis. In Series A, we will correlate the pharmacokinetic (PK) profile and hemodynamic effect of single administration of R-100 (3, 10, 20, 30 mg/kg), with a 1-week washout period between successive dose levels. Animals will be monitored for 24 h to collect continuous hemodynamic data and intermittent plasma concentrations of R-100 and its metabolites. In Series B, we will evaluate the most promising 2 doses of R-100 from Series A, by carrying out a repeat-dose study of R-100 administered q6h for a period of 3 days. The hemodynamic effects of R-100 will be correlated with plasma peak and trough concentrations of R-100 and its metabolites obtained q6h. In Series C, we will evaluate the emergence of tachyphylaxis to R-100 in a 2-week repeat-dose study (q6h) utilizing the optimal dose determined in Series B, wherein hemodynamics will be correlated with plasma PK determinations as in Series B. Taken together, these studies will establish in a large animal model: 1) the relevant dose range, 2) the PK profile, 3) the PD profile, and 4) the extent of tolerance. Aim #2: Establish the in vitro metabolic profile of R-100 induced by exposure to human liver and intestinal microsomes. Prominent metabolites will be synthesized and evaluated for secondary metabolism in human microsomes. These findings will be further refined by identifying human CYPP450 enzymes that are responsible for metabolic transformation of R-100. Lastly, we will determine if R-100 inhibits major human CYP450 enzymes. The results of the proposed studies are expected to serve as the basis for a Phase 1a IND application to the FDA examining the safety and efficacy of oral R-100 in subjects with stable essential HTN. Follow-on Phase 1b repeat-dose 2-week studies will additionally establish whether R-100 induces tolerance in man. PUBLIC HEALTH RELEVANCE: Refractory peripheral hypertension is a frequent and life-threatening condition that increases the risk of cardiovascular events such as stroke and aortic aneurysm. We are developing a novel drug that targets the basic mechanisms of refractory hypertension and has been shown to be effective in pilot studies in a small animal model. We now propose to define the value of our technology in a definitive clinically-relevant large animal model of hypertension.

描述（由申请人提供）：硝酸盐治疗周围性高血压（HTN）的疗效有限，因为其通过使线粒体醛脱氢酶失活而快速诱导速反应。引入无耐受性诱导的硝酸盐疗法将是一个重要的商业机会，并解决一个未得到满足的主要医疗需求。Radikal Therapeutics （RTX）正在开发R-100，这是一种由以下共价键形成的小分子药物：1)释放一氧化氮（NO）的有机硝基血管扩张剂结构域，2)作为活性氧降解催化剂的吡咯烷类氮氧化物结构域：超氧化物歧化酶（SOD）模拟物，过氧化氢解毒的过氧化氢酶模拟物，以及过氧亚硝酸盐分解催化剂。R-100已在离体和体内啮齿类动物系统中被证明是一种强大的血管扩张剂，不会诱导耐受性。R-100尚未被评估是否能诱导长期服用的有意识大型动物的硝酸盐耐受性，这是其药物开发的一个关键里程碑。目的1：建立R-100在有意识、动态、大型HTN动物模型中的药效学（PD）特征。一系列血流动力学研究将在患有HTN的有意识、仪器化、动态和遥测的小型猪中进行，HTN继发于血管内产生的单侧肾血管狭窄。在A系列中，我们将把单次给药R-100（3、10、20、30 mg/kg）的药代动力学（PK）谱和血流动力学效应与连续剂量水平之间的1周洗脱期联系起来。动物监测24小时，收集连续血流动力学数据和R-100及其代谢物的间歇性血浆浓度。在B系列中，我们将评估A系列中最有希望的两种R-100剂量，通过对R-100进行重复剂量研究，每隔6小时给药3天。R-100的血流动力学效应将与血浆中R-100及其代谢物的峰谷浓度相关。在C系列中，我们将利用B系列中确定的最佳剂量，在一项为期2周的重复给药研究（q6h）中评估R-100快速反应的出现，其中血液动力学将与血浆PK测定相关联，与B系列中一样。总之，这些研究将在大型动物模型中建立：1)相关剂量范围，2)PK谱，3)PD谱，4)耐受性程度。目的2：建立暴露于人类肝脏和肠道微粒体诱导的R-100体外代谢谱。将合成突出的代谢物，并评估人类微粒体的次级代谢。这些发现将通过鉴定负责R-100代谢转化的人类CYPP450酶进一步完善。最后，我们将确定R-100是否抑制主要的人类CYP450酶。拟议研究的结果预计将作为向FDA申请1a期IND的基础，以检查口服R-100在稳定的必需HTN患者中的安全性和有效性。后续1b期重复给药2周的研究将进一步确定R-100是否诱导人类耐受。