Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States.
J Med Chem. 2024 May 23;67(10):7825-7835. doi: 10.1021/acs.jmedchem.3c02413. Epub 2024 May 10.
Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator . Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.
肌球蛋白激活已被证明是治疗射血分数降低的心力衰竭的一种可行方法。在这里，我们报告了 nelutroctiv（）的发现，这是一种选择性的肌钙蛋白激活剂，用于心血管状况降低心脏收缩力的患者。Nelutroctiv 的发现始于高通量筛选，该筛选鉴定出化合物 ，这是一种肌肉选择性的心肌收缩蛋白激活剂，没有磷酸二酯酶-3 活性。对 的药物样特性进行优化导致了磺酰胺和苯胺取代基的替换，这导致了改善的药代动力学 (PK) 特征和减少了人类药物相互作用的潜力。与肌球蛋白激活剂相比，优化后的先导化合物的心脏超声心动图评估显示，分数缩短呈浓度依赖性增加，并且药效学窗口得到改善。总体而言，Nelutroctiv 被发现具有所需的选择性、相对于肌球蛋白激活剂的有利药效学窗口，以及支持临床开发的临床前 PK 特征。
