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

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

  • J Med Chem. 2024 May 23;67(10):7825-7835. doi: 10.1021/acs.jmedchem.3c02413.
Antonio Romero 1,  Luke Ashcraft 1,  Aroop Chandra 1,  Vincent DiMassa 1,  Peadar Cremin 1,  Scott E Collibee 1,  Chihyuan Chuang 1,  James Hartman 1,  Darren T Hwee 1,  David St Jean 1,  Justin Malinowski 1,  Mikkel DeBenedetto 1,  David Moebius 1,  Joshua Payette 1,  Richard Vargas 1,  John Yeoman 1,  Alykhan Motani 1,  Jeffrey Reagan 1,  Fady I Malik 1,  Bradley P Morgan 1
Affiliations

Affiliation

  • 1 Cytokinetics, Inc., 350 Oyster Point Boulevard, South San Francisco, California 94080, United States.
PMID: 38729623 DOI: 10.1021/acs.jmedchem.3c02413
Abstract

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.

Figures
Products