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）：外周高血压（HTN）的硝酸盐疗法由于速度降低了线粒体醛脱氢酶而迅速诱导了速度，因此在疗效中受到限制。引入硝酸盐疗法没有耐受性诱导将代表一个很大的商业机会，并满足了主要的未满足医疗需求。 Radikal Therapeutics（RTX）正在开发R-100，这是一种小分子剂，由以下相互链接形成：1）一个有机硝基化舒张剂结构域，释放一氧化一氧化氮（NO）和2）吡咯烷二硝基氧化物域，该结构域是催化作用的催化剂，它是反应性氧化物的催化作用（过氧化氢酶模拟于过氧化氢排毒和过氧亚硝酸盐分解催化剂。 R-100在离体和体内啮齿动物系统中已被证明是一种强大的血管扩张剂，不会引起耐受性。尚未评估R-100在慢性剂量有意识的大动物中诱导硝酸盐耐受性，这是其药物发育中的关键里程碑。 AIM＃1：建立R-100的药效学（PD）轮廓，在HTN的有意识的，卧床，大动画模型中，将在有意识，仪器，卧床和远程远程仪的Minipigs中进行一系列血液动力学研究，其继发于内血管内部生成的，单一的，同侧的，修改后的htn。在A系列中，我们将将单个施用R-100（3、10、20、30 mg/kg）的药代动力学（PK）谱和血液动力学效应相关联，并且连续剂量水平之间进行了1周的洗涤周期。将监测动物24小时，以收集R-100及其代谢产物的连续血流动力学数据和间歇性血浆浓度。在B系列中，我们将通过对A级的R-100进行Q6H的重复剂量研究来评估A系列中最有希望的2剂R-100剂量。 R-100的血液动力学作用将与血浆峰和R-100的谷浓度及其代谢产物相关。在C系列中，我们将在一项为期2周的重复剂量研究（Q6H）中评估速度的出现，利用B系列中确定的最佳剂量，其中血液动力学将与B系列的血浆PK确定相关。 宽容。 AIM＃2：建立暴露于人肝和肠微粒体的R-100的体外代谢谱。将合成显着的代谢物并评估人类微粒体的继发代谢。这些发现将通过确定负责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是否抑制了主要的人类CYP450酶。拟议研究的结果预计将作为FDA阶段应用的基础，以检查口服R-100在具有稳定必需HTN的受试者中的安全性和有效性。后续1B重复剂量2周的研究还将确定R-100是否诱导人类的耐受性。 公共卫生相关性：难治性外周高血压是一种频繁且威胁生命的疾病，可增加心血管事件（例如中风和主动脉瘤）的风险。我们正在开发一种针对难治性高血压的基本机制的新型药物，并已被证明在小动物模型中有效研究。现在，我们建议在确定的临床上与高血压的大型动物模型中定义技术的价值。