Fragment-Based Drug Discovery for Diseases of the Central Nervous System

Although diseases of the central nervous system are among the most devastating to patients and their families, disease modifying treatments have lagged behind other therapeutic areas. Current treatments were primarily discovered by serendipity and address disease symptoms. In the genomic era, understanding of CNS biology and disease associated mutations is growing thereby identifying a new series of putative targets. As CNS biology matures, there is growing need for a discovery paradigm that addresses the unique needs of CNS therapeutics, namely the ability of compounds to cross the blood-brain-barrier. The physiochemical properties of CNS therapeutics have been identified based upon historic data and may be used to guide discovery efforts. One notable variable is that the compounds should be low molecular weight. In this chapter, we discuss the merits of fragment-based lead discovery and how it may be used to address the challenges of CNS drug discovery. We also summarize practical strategies for library design and screening. Finally, we summarize examples of how fragments may be optimized into lead compounds.