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

项目总结 总部位于印第安纳州的一家小企业Vasculonics正在开发一种新的疗法来减缓癌症的进展 肺动脉高压(PAH)是一种病死率很高的衰弱疾病。血管电子技术是一种 代谢不对称二甲基二甲基精氨酸二甲氨基水解酶的新型调节剂 精氨酸(ADMA)与心脏和肺脏的重要分子机制 PAH的病理学。在PAH患者和临床前模型中，ADMA水平较高，DDAH水平较低。在……里面 除了减少一氧化氮的合成，高水平的ADMA还会导致线粒体功能障碍，细胞死亡， 炎症和纤维化。持续高ADMA水平可促进进行性血管重塑 PAH患者心肌肥厚。DDAH缺乏促进PAH和PAH的概念证明 心血管疾病，在转基因动物中恢复DDAH改善了内皮功能， 并改变了肺和心脏的病理，已经得到证实。目前，药物调节 DDAH途径不可用。Vasculonics正在开发一种新型的DDAH小分子调制剂 减少病理水平的ADMA和进行性血管病变的PAH。 Vasculonics已经确定VN-317是一种新的先导系列，它增强了DDAH-1的转录 基于DDAH启动子的筛选。在PAH的临床前模型中，VN-317通过以下方式显示出强大的疗效 减少肺动脉闭塞，改善心肺功能。Vasculonics有 研究了该化学支架的构效关系(SAR)，结果表明 用于DDAH调制的SAR。为了推进VN-317结构等级的临床选型 候选公司Vasculonics正在提议优化该系列的类药物特性和其他 化学支架设计为二苯乙烯类化合物。结构上不同的化合物将按顺序 在Tier1和Tier2试验中评估理想的体外和体内药物能力特征。活体内 将证实两种结构不同的导联对减少大鼠SUGEN-PAH进展的有效性。 缺氧模型。这些研究有望使选择符合要求的候选分子成为可能。 推动两个铅分子进入晚期非临床CMC和安全性研究的药物能力和有效性。 Vasculonics组建了一支经验丰富的科学和药物开发团队来追求Ind 使研究成为可能，并将这一潜在的新疗法推广到PAH患者。拟议的研究将 帮助获得未来的赠款和投资者的资金，用于进一步的发展。存在着一个重要的市场 PAH治疗，估计价值超过40亿美元。因此，一种新的疾病修正 治疗预计将产生重大的医疗和商业影响。

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.