Pu-Ping Lu

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.

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application.

Significance Defects in myosin function are linked to a number of widespread and debilitating diseases, including asthma, chronic obstructive pulmonary disease, and hypertrophic cardiomyopathy. We report here the discovery of an allosteric site that modulates myosin motor function with high specificity that opens the path toward new therapeutic solutions. Identification of specific antimyosin drugs that significantly alter a motor’s function is an imperative first step toward the development of targeted and effective treatments for such diseases. Highly specific drugs against different members of the superfamily would also provide exquisite tools to investigate in cells their functional role. Additionally, detailed, high-resolution studies of the interaction of drugs with their myosin targets provide insights into the molecular mechanism of motor function. Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the “recovery stroke” transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.

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

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.