We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.Over-production of proinflammatory cytokines contributes to the progression of pathology in a diverse array of diseases, 1-5 and the recent approval of protein therapies 5-8 that seek to control the level or activity of proinflammatory cytokines provides a proof-of-concept for targeting proinflammatory cytokine levels in drug discovery. However, the macromolecular therapeutic approach is not as amenable to clinical use in some diseases, such as central nervous system (CNS) disorders, creating an unmet need for small molecule, brain-penetrant compounds as new classes of disease-modifying drugs. An accumulating body of evidence from animal model studies and clinical observations supports the concept 1,3,4,9,10 that development of such therapies for CNS disorders could have potential impact on both acute and chronic disorders as diverse as Alzheimer's disease (AD), stroke, traumatic brain injury, neuropathic pain, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, agerelated macular degeneration, and non-AD dementias. The prevailing hypothesis in this regard is that targeting the up-regulation of proinflammatory cytokine production by activated glia, the main cellular source of cytokines in the CNS, will alter disease progression through attenuation of the subsequent neuronal synaptic dysfunction, the cellular basis of clinical symptoms and behavioral alterations. However, there are no such current therapies available and there are no consensus molecular targets for such discovery efforts. The current state of the art requires, therefore, the use of the more classical and unbiased functional approach to drug discovery. 11 *To Whom Correspondence Should be Addressed: Phone: 312-503-0656, FAX: 312-503-0007, E-mail: m-watterson@northwestern.edu.
SUPPORTING INFORMATION AVAILABLE:The contents of Supporting Information include the following: details of synthetic procedures, analytical chemistry methods, physical property determinations, NMR spectra, and biological procedures, including screening data for oral bioavailability.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affec...