Discovery of functionally selective Alzheimer's disease therapeutics

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Abstract The prevalence of Alzheimer's disease (AD) and the associated financial and caregiver burden is projected to escalate dramatically unless disease-modifying treatments are discovered. Our research is focused on addressing this urgent unmet medical and societal need through the discovery and development of pharmacotherapies capable of averting or delaying the progression of AD. Brain inflammation initiated by chronic oxidative-nitrosative stress is a proven component of the pathogenic cascade leading to mild cognitive impairment (MCI) and AD. When surplus inflammatory nitric oxide and superoxide molecules combine they form the brain-impairing reactive species peroxynitrite. This perpetuates inflammation resulting in the progressive neurodegeneration observed in AD. Our innovative approach consists of managing two processes associated with inflammatory disease progression. The first involves interrupting the cycle of peroxynitrite generation by suppressing unsafe elevations in nitric oxide triggered by oxidative stress, and the second involves enhancing resilience to and recovery from inflammatory insults by facilitating the secretion of brain-derived neurotrophic factor (BDNF). A single stress-activated chaperone protein is mechanistically capable of both mediating BDNF secretion and regulating nitric oxide levels under proinflammatory conditions. Preliminary studies have identified chemotype starting points for further CNS drug development which have the desired dual functional selectivity profile for this target receptor. Our plan is to optimize the CNS drug-like properties of these functionally selective chemotypes with the goal of developing medicines that can significantly modify the course of MCI/AD.