Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5′-triphosphate (ATP) turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

a b s t r a c tWe measured Dechlorane Plus (DP) and its dechlorinated analogs in the blood and milk from women living in e-waste recycling sites in Wenling of Taizhou region, China (n ¼ 49). Both syn-DP and anti-DP were detected in all samples. Another compound, Cl 11 -DP, was detected in 45% and 84% of milk and serum samples, respectively. DP levels in blood and milk from residents living in the local environment >20 yrs (R 20 group) were significantly higher than those living in Taizhou <3 yrs (R 3 group) (p < 0.05). The milk/serum partition coefficient from the same women was approximately 0.43 and 0.47 for syn-DP and anti-DP, respectively. A similar value in milk compared with anti-DP/ P DPs (f anti ) in serum suggested that stereoselective DP bio-accumulation did not occur during the DP transport from blood to milk. This result indicate that DP can bio-accumulate in blood and milk with the low milk/serum partition coefficient and similar blood and milk stereoselective bio-accumulation profiles.

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.