EDG-7500 is a diastolic-selective cardiac sarcomere modulator (d-CSM) that preferentially inhibits cardiac myofibril ATPase activity with EC25 value of 3.0 nM at diastolic calcium levels, with limited activity at systolic calcium levels (EC25>100 uM).
EDG-7500 acts through indirect modulation of myofibril ATPase enzymatic activity that requires the regulatory light chain (RLC).
EDG-7500 preferentially inhibits DMSO normalized ATPase activity of porcine ventricle full length (VFL) myosin but do not inhibit porcine left ventricle myosin subfragment-1 (VS1).
EDG-7500 shows no inhibitory effects on DMSO normalized ATPase activity in chicken gizzard smooth muscle myofibrils.
EDG-7500 is an allosteric modulator of myosin ATPase activity dependent upon a molecular context, which requires the RLC residing within a fully intact myosin structure.
EDG-7500 shows phenotype preferentially promoting relaxation and preserving cardiac reserve without impacting systolic function in treated tissue and animals.
DG-7500 does not alter myosin SRX state, but decreases Ca2+-sensitivity of force independent of mutation in human hypertrophic cardiomyopathy (HCM) cardiac strips.
Chronic EDG-7500 normalized LV filling pressure and prevented pathological cardiac remodeling while preserving normal systolic function and cardiac reserve in R403Q swine.