Discovery of , the First Direct Fast Skeletal Muscle Troponin Activator.

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.

Successful treatment of ventriculostomy-associated meningitis caused by multidrug resistant coagulase-negative Staphylococcus epidermidis using low-volume intrathecal daptomycin and loading strategy.

Objective: To report successful use of low-volume intrathecal (IT) daptomycin and loading strategy for the treatment of ventriculostomy-associated meningitis.

Case Summary: A 23-year-old man with a history of multiple ventriculoperitoneal shunt revisions resulting from multidrug-resistant Staphylococcus epidermidis shunt infection presented with meningitis despite suppressive antibiotic therapy. After source control surgery, the patient improved with intravenous daptomycin plus IT vancomycin.

Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

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.

Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac Myosin.

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.