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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 (CK-136), 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 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1Rled 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. In vivoechocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. 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.

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit 2increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of 1and 2was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of CK-963and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition. Rat echocardiography studies using CK-963demonstrated concentration-dependent increases in cardiac fractional shortening up to 95%. Isothermal calorimetry studies confirmed a direct interaction between CK-963and a cardiac troponin chimera with a dissociation constant of 11.5 ± 3.2 μM. These results provide evidence that direct activation of cardiac troponin without the confounding effects of PDE-3 inhibition may provide benefit for patients with cardiovascular conditions where contractility is reduced.

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Background:Current heart failure (HF) therapies improve cardiac energy balance and prolong survival by unloading the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropic medications, also termed calcitropes, stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. Myotropes are a new class of agents that activate the sarcomere directly, independent of cAMP and calcium. We hypothesize that a novel myotrope, troponin activator (TA1), increases contractility without the deleterious myocardial energetic impact of calcitrope dobutamine (DOB).Methods:We determined the pharmacodynamics of TA1 ex vivoand in vivoin anesthetized normal rats. Isolated rat hearts were perfused with incremental concentrations of TA1 or DOB to compare their effect on cardiac contractility and high-energy phosphate concentrations using 31P NMR spectroscopy.Results:A dose dependent increase in contractility was observed in vivoby echocardiography after acute administration of TA1. In isolated hearts, increasing concentrations of TA1 and DOB similarly increased rate pressure product (RPP), which is a product of developed pressure (DevP) and heart rate (HR). At equivalent doses (DOB 120 nM, TA1 60 nM), TA1 increased DevP more and HR less compared to DOB. DOB decreased phosphocreatine (PCr) to ATP ratio and free energy of ATP hydrolysis (ΔG~ATP) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased RPP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG~ATP.Conclusions:Here we describe a novel myotrope, TA1, that increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, TA1 may represent a superior alternative to traditional inotropes in HF management.