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 (t
1/2) 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 t
1/2 similar to predictions and was able to reach
steady state concentration within the desired two-week window.
GH exerts an acute vascular effect independent of both systemic and local IGF-I production, and this effect is likely via direct action on GH receptors and eNOS in the vascular endothelium.
In a porcine model of HF, SCS induces significant remodelling of cardiac sympathetic innervation over the peri-infarct and infarct regions and is associated with improved LV function and reduced myocardial norepinephrine spillover.
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