Key result
Omecamtiv mecarbil was discovered and optimized as the first selective small molecule activator of cardiac myosin, demonstrating increased cardiac contractility in preclinical models.
Describes the medicinal chemistry discovery and optimization process of omecamtiv mecarbil, the first selective small molecule activator of cardiac myosin.
Supports myosin activator development for systolic dysfunction; leaves open clinical translation from animal models.
We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.
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Morgan et al. (2010) studied Systolic heart failure. Omecamtiv mecarbil was evaluated on Cardiac myosin ATPase activity (AC40) and fractional shortening (FS). Omecamtiv mecarbil was discovered and optimized as the first selective small molecule activator of cardiac myosin, demonstrating increased cardiac contractility in preclinical models.
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