Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy.
Chuang C, Collibee S, Ashcraft L, Wang W, Vander Wal M, Wang X, Hwee DT, Wu Y, Wang J, Chin ER, Cremin P, Zamora J, Hartman J, Schaletzky J, Wehri E, Robertson LA, Malik FI, Morgan BP.
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 <b>1</b>. The important advancement of the optimization was discovery of an Indane analogue (<b>12</b>) 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 (<i>t</i><sub>1/2</sub>) 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 <i>in vivo</i> with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human <i>t</i><sub>1/2</sub> similar to predictions and was able to reach steady state concentration within the desired two-week window.