Duchenne muscular dystrophy is a devastating, X-linked disease that affects approximately one in 3,000 boys and is characterized by muscle weakness, loss of ambulation and eventual respiratory and cardiac complications that result in the death of these young men in their late teens or early twenties. There is no cure for this rare muscle wasting disorder. In an ongoing effort to identify new treatments for DMD patients, we are using a proprietary drug discovery platform technology (developed by PTC Therapeutics) called GEMS (Gene Expression Modulation by Small-molecules) to identify small molecules that up- or down-regulate the production of proteins. GEMS has proven to be a very robust technology that can address difficult drug targets. We have performed high throughput screens against four targets believed to be medically relevant hi DMD. Compounds have emerged from the screen that demonstrate sufficient activity, selectivity and potency in cell-based assays to merit further characterization and chemical optimization. Lead optimization is a complex and iterative process of refining the structure of the chemical scaffolds identified hi HTS in order to improve the activity, selectivity and specificity of the compound as well as their drug characteristics.
The aims of this proposal are to explore the chemical space surrounding these molecules to evaluate the structure-activity relationships (SAR) for these molecules. SAR is the relationship between chemical structure and biological (in vitro and in vivo) and pharmacological activity for a given series of compounds. Four Core groups consisting of Biology, Chemistry, Pharmacology and Efficacy Assessment Cores have been assembled to work in a concerted effort to rigorously characterize and optimize the biological, chemical, pharmacological and in vivo efficacy of the compounds that modulate production of each of the four targets. The objective of the lead optimization process is to increase potency, selectivity and pharmaceutical properties of the classes of chemicals such that ultimately a single compound per target is chosen to perform toxicology tests in preparation for studies in humans. The ultimate goal of this effort is to identify at least two Development Candidates that will be tested in a series of studies to enable submission of a minimum of two IND (Investigational New Drug) applications to the FDA.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Porter, John D
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University of Pennsylvania
Schools of Medicine
United States
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Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91