Novel antifibrotic small molecules for the treatment of heart failure

 描述（由申请人提供）：本项目的总体目标是开发更安全、更有效的心力衰竭治疗药物。心脏病是世界范围内的头号死因，也是女性的头号杀手-超过所有癌症的总和。在美国，每9例死亡中就有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 的心力衰竭患者在确诊后5年内死亡。显然，非常需要治疗心力衰竭的破坏性影响的疗法。 心脏肥大是心力衰竭的主要预测因素。最初，心脏通过诱导心肌细胞肥大生长来适应压力，以承受增加的心肌壁应力。然而，长时间的应激导致适应不良的变化，包括由于持续的心脏肌成纤维细胞而导致的纤维化和重塑增加。随着时间的推移，心脏功能下降，最终导致心力衰竭。对应激（心肌梗死或压力超负荷）的初始反应的关键成分是TGF-β。尽管TGF-β水平升高最初对于损伤后的组织修复和重塑是重要的，但TGF-β的持续过量产生导致心肌纤维化和适应不良的心脏肥大的发展。 NovoMeidine开发了一系列新型小分子，可防止正常成纤维细胞转化为肌成纤维细胞表型。该系列中的化合物之一NM 922在心力衰竭的小鼠横向主动脉缩窄（TAC）模型中进行了测试。从收缩后6周开始，每天施用NM 922，持续10周。在心脏肥大和心力衰竭发作后用NM 922长期治疗导致心肌胶原蛋白形成减少和不良重塑减弱，同时保留左心室射血分数。 本项目的具体目的是：1）完成额外的安全性试验并确定至少一种备用候选药物; 2）选择经口给药的溶剂/制剂; 3）定义最佳给药窗口并证明经口给药时在小鼠TAC模型中的体内疗效。在TAC小鼠模型中口服有效的优化候选药物将进入II期，在那里它们将在小型和大型心力衰竭动物模型中进行额外的测试，以及额外的预处理。 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.