2. Academic Validation
  3. Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy

Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy

  • J Med Chem. 2021 Oct 14;64(19):14142-14152. doi: 10.1021/acs.jmedchem.1c01290.
Chihyuan Chuang 1,  Scott Collibee 1,  Luke Ashcraft 1,  Wenyue Wang 1,  Mark Vander Wal 1,  Xiaolin Wang 1,  Darren T Hwee 1,  Yangsong Wu 1,  Jingying Wang 1,  Eva R Chin 1,  Peadar Cremin 1,  Jeanelle Zamora 1,  James Hartman 1,  Julia Schaletzky 1,  Eddie Wehri 1,  Laura A Robertson 1,  Fady I Malik 1,  Bradley P Morgan 1
Affiliations

Affiliation

  • 1 Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States.
PMID: 34606259 DOI: 10.1021/acs.jmedchem.1c01290
Abstract

Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac Myosin inhibitor that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery of an Indane analogue (12) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life (t1/2) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial Cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.

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