Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility

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 1R 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. In vivo echocardiography 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.