Preclinical Development of a Novel Disease Modifying Therapy for Pulmonary Arterial Hypertension

肺动脉高压新型疾病修饰疗法的临床前开发

• 批准号: 10054277
• 负责人: Jaipal Singh
• 金额: $ 43.12万
• 依托单位: VASCULONICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054277
• 关键词: Animals; Arginine; Arteries; Binding Proteins; Biological Assay; Biological Availability; Blood Vessels; Businesses; Cardiac; Cardiovascular Diseases; Cell Death; Characteristics; Chemicals; Chemistry; Clinical; Data; Development; Disease; Disease Progression; Drug Kinetics; Drug Targeting; Endothelin; Endothelium; Enzymes; Fibrosis; Functional disorder; Funding; Future; Genetic Transcription; Goals; Grant; Heart; Heart Hypertrophy; Hepatocyte; Hypoxia; In Vitro; Indiana; Inflammation; Lead; Life; Lung; Medical; Mesenchymal; Metabolic; Microsomes; Mitochondria; Modeling; Molecular; Molecular Target; Monocrotaline; Nitric Oxide; Oral; Pathologic; Pathology; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Property; Pulmonary artery structure; Quality of life; Rattus; Respiratory physiology; Secure; Series; Solubility; Stilbenes; Structure; Structure-Activity Relationship; Survival Rate; Technology; Therapeutic; Toxicology; Toxin; Transgenic Animals; Universities; Vascular Diseases; Vascular remodeling; Vasodilation; Vasodilator Agents; base; candidate selection; clinical candidate; design; dimethylargininase; drug candidate; drug development; experience; heart function; improved; in vivo; inhibitor/antagonist; lead candidate; lead optimization; lead series; mimetics; mitochondrial dysfunction; mortality; novel; novel strategies; novel therapeutics; pre-clinical; preclinical development; pressure; promoter; pulmonary arterial hypertension; reduce symptoms; restoration; safety study; scaffold; small molecule; targeted agent; targeted treatment; transgene expression

PROJECT SUMMARY Vasculonics, an Indiana-based small business is developing a novel therapy to reduce progression of pulmonary arterial hypertension (PAH), a debilitating disease with high mortality. Vasculonics technology is a novel modulator of dimethylarginine dimethylaminohydrolase (DDAH) which metabolizes asymmetric dimethyl arginine (ADMA) and an important molecular mechanism contributing to the pulmonary as well as cardiac pathology in PAH. High levels of ADMA and reduced DDAH occur in patients and preclinical models of PAH. In addition to reducing nitric oxide synthesis, high levels of ADMA induce mitochondrial dysfunction, cell death, inflammation and fibrosis. Persistent high ADMA levels can contribute to the progressive vascular remodeling and cardiac hypertrophy observed in PAH. The proof of concept that deficiency of DDAH promoted PAH and cardiovascular disease, and that restauration of DDAH in transgenic animals improved endothelial function, and modified the pathology in the lung and the heart, have been demonstrated. Currently, drugs modulating the DDAH pathway are not available. Vasculonics is developing a novel small molecule modulator of DDAH to reduce pathological levels of ADMA and the progressive vasculopathy in PAH. Vasculonics has identified VN-317 as a novel lead series which enhanced transcription of DDAH-1 in a DDAH promoter based screen. In a preclinical model of PAH, VN-317 has shown robust efficacy by reducing occlusion of lung arteries, and improving lung and cardiac functions. Vasculonics has investigated the structure-activity relationship (SAR) of this chemical scaffold and demonstrated clear SAR for DDAH modulation. In order to advance the VN-317 structural class for the selection of a clinical candidate, Vasculonics is proposing to optimize the drug-like properties of the series and additional chemical scaffold designed as stilbene-mimetics. Structurally distinct compounds will be sequentially evaluated for ideal in vitro and in vivo drug-ability characteristics in tier1 and tier2 assays. The in vivo efficacy of two structurally distinct leads will be confirmed for reducing PAH progression in a rat Sugen- hypoxia model. These studies are expected to enable selection of candidate molecules with desired drug-ability and efficacy to propel two lead molecules to late stage non-clinical CMC and safety studies. Vasculonics has assembled a highly experienced scientific and drug development team to pursue IND enabling studies and advance this potentially new therapy to PAH patients. The proposed studies will help secure future grants and investor funding for further development. A significant market exists for PAH therapy with an estimated value in excess of $4 billion. Therefore, a new disease modifying therapy is expected to have a major medical as well as commercial impact.

项目摘要 一家印第安纳州的小型企业Vasculonics正在开发一种新型疗法，以减少 肺动脉高压（PAH），一种具有高死亡率的使人衰弱的疾病。 Vasculonics技术是 二甲基精氨酸二甲基氨基氢化酶（DDAH）的新型调节剂，该二甲基氢化酶（DDAH）代谢不对称二甲基 精氨酸（ADMA）和有助于肺和心脏的重要分子机制 PAH的病理学。 PAH的患者和临床前模型发生高水平的ADMA和DDAH。在 除了减少一氧化氮合成外，高水平的ADMA诱导线粒体功能障碍，细胞死亡， 炎症和纤维化。持续的高级ADMA水平可能有助于进行性血管重塑 和心脏肥大在PAH中观察到。 DDAH缺乏促进PAH的概念证明和 心血管疾病以及DDAH在转基因动物中的餐馆改善了内皮功能， 并已证明了肺和心脏中的病理。目前，药物调节 DDAH途径不可用。 Vasculonics正在开发一种新型的DDAH的小分子调节剂 降低PAH中ADMA的病理水平和进行性血管病。 Vasculonics已将VN-317识别为一个新的铅系列，增强了DDAH-1的转录 基于DDAH启动子的屏幕。在PAH的临床前模型中，VN-317通过 减少肺动脉阻塞，并改善肺和心脏功能。脉管学具有 研究了该化学支架的结构活性关系（SAR），并证明了清晰 用于DDAH调制的SAR。为了推进VN-317的结构类别，以选择临床 候选人，Vasculonics提议优化该系列的药物样性能和其他 化学脚手架设计为Stilbene-Mimetics。结构上不同的化合物将是顺序的 评估了TIER1和TIER2分析中的理想体外和体内药物能力特征。体内 将确认两个结构上不同铅的功效，以降低大鼠sugen-的PAH进展 缺氧模型。预计这些研究将能够选择所需的候选分子 吸毒性和功效可以将两个铅分子推向晚期非临床CMC和安全研究。 Vasculonics已组建了一个经验丰富的科学和药物开发团队，以追求IND 为PAH患者提供研究并推进这种潜在的新疗法。拟议的研究将 帮助确保未来的赠款和投资者资助以进一步发展。存在一个重要的市场 PAH治疗的估计价值超过40亿美元。因此，一种新的疾病正在修改 预计治疗将具有重大的医疗和商业影响。