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

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.