Novel antifibrotic small molecules for the treatment of heart failure

 描述(由申请人提供)：该项目的总体目标是开发更安全、更有效的治疗心力衰竭的药物。心脏病是世界范围内的头号死因，也是女性的头号杀手--超过了所有癌症的总和。在美国，每9例死亡病例中就有1例与心力衰竭有关。由于急性心肌梗死死亡率的降低，心力衰竭的患病率急剧上升。大约一半 患心力衰竭的人中有5%在确诊后5年内死亡。显然，治疗心力衰竭的破坏性影响是非常有必要的。心肌肥厚是心力衰竭的主要预测指标。最初，心脏通过诱导心肌细胞肥大生长来适应应激，以承受增加的心肌壁应力。然而，长期的应激会导致不适应的变化，包括由于持续性的心肌成纤维细胞而导致的纤维化和重构的增加。随着时间的推移，心功能下降，最终导致心力衰竭。对压力(心肌梗死或压力超负荷)的初始反应的一个关键成分是转化生长因子-β。尽管转化生长因子-β的高水平最初对损伤后的组织修复和重塑很重要，但持续的转化生长因子-β的过度产生会导致心肌纤维化和适应性不良的心肌肥厚的发展。NovoMedex已经开发出一系列新的小分子，可以防止正常成纤维细胞向肌成纤维细胞表型的转化。本系列中的化合物之一NM922在心力衰竭的小鼠横向主动脉缩窄(TAC)模型上进行了测试。NM922从狭窄后6周开始，每天给药10周。在心脏肥厚和心力衰竭发作后，长期服用NM922可以减少心肌胶原的形成，并在保留左心室射血分数的情况下减轻不利的重构。该项目的具体目标是：1)完成额外的安全性测试，并确定至少一个备用候选药物；2)选择口服给药的载体/配方；以及3)确定最佳给药窗口，并在口服时在小鼠TAC模型中展示体内疗效。在TAC小鼠模型中口服有效的优化候选药物将进入第二阶段，在那里他们将在心力衰竭的小动物和大动物模型上接受额外的测试，以及额外的 临床毒理学测试。

 DESCRIPTION (provided by applicant): The overall goal for this project is the development of safer, more effective drugs for the treatment of heart failure. Heart disease is the number one cause of death worldwide and the #1 killer of women - more than all forms of cancer combined. One in 9 deaths in the US are heart failure related. The prevalence of heart failure has risen dramatically as a result of the reduction in mortality from acute myocardial infarction. About half of the people who develop heart failure die within 5 years of diagnosis. Clearly, there is a significant need for therapies to treat the devastating effects of heart failure. Cardiac hypertrophy is a major predictor of heart failure. Initially, the heart adapts to stress by inducin hypertrophic growth of cardiomyocytes in order to withstand the increased myocardial wall stress. However, periods of prolonged stress result in maladaptive changes, including increased fibrosis and remodeling as a result of persistent cardiac myofibroblasts. Over time cardiac function decreases, which ultimately results in heart failure. A key component of both the initial response to stress (myocardial infarct or pressure overload) is TGF-β. Although elevated levels of TGF-β are initially important for tissue repair and remodeling after injury, sustained overproduction of TGF-β leads to the development of myocardial fibrosis and maladaptive cardiac hypertrophy. NovoMedix has developed a novel series of small molecules that prevent the conversion of normal fibroblasts to the myofibroblast phenotype. One of the compounds in this series, NM922, was tested in a mouse transverse aortic constriction (TAC) model of heart failure. NM922 was administered daily for 10 weeks starting at 6 weeks post constriction. Chronic treatment with NM922 following the onset of cardiac hypertrophy and heart failure resulted in reduced myocardial collagen formation and attenuated adverse remodeling with preservation of left ventricular ejection fraction. The specific aims for this project are: 1) complete additional safety testing and identify at least one back-up candidate; 2) select vehicle/formulation for oral dosing; and 3) define optimal dosing window and demonstrate in vivo efficacy in a mouse TAC model when administered orally. Optimized drug candidates that are effective orally in the TAC mouse model will advance to Phase II, where they will undergo additional testing in both small and large animal models of heart failure as well as additional pre clinical toxicology testing.