P4–428: Glia as a therapeutic target: Selective suppression of human amyloid–beta–induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration

Abstract

Increasing evidence has identified excessive or uncontrolled neuroinflammation from chronically activated glia as a contributor to progression of Alzheimer's disease (AD)–related pathophysiology in animal models, consistent with diverse clinical observations. Our hypothesis is that restoration of excessive production of proinflammatory cytokines by activated glia back towards basal will result in neuroprotection. to test upregulation of glial proinflammatory cytokine production as a potential therapeutic target for AD. The goal is to develop small molecule compounds that selectively suppress proinflammatory cytokine upregulation in the brain, and test their effectiveness in attenuation of AD–relevant pathophysiology progression. We used a new approach called de novo lead compound discovery where we started with an inactive chemical fragment and performed chemical diversifications based on a series of decision gates. This chemistry platform was integrated with a hierarchal biological screen focused on selective inhibition of proinflammatory cytokine production by activated glia, along with a series of decision gates based on oral bioavailability, metabolic stability, brain uptake, and initial toxicity screens. We developed a novel class of orally bioavailable, CNS–penetrant, small molecule compounds that selectively suppress proinflammatory cytokine upregulation in the brain, leading to attenuation of AD–relevant pathophysiology progression. The initial lead compound, termed MW01–5–188WH, is a selective inhibitor of proinflammatory cytokine production by activated glia in the hippocampus (Ralay Ranaivo et al., 2006, J Neurosci 26:662–670). In a mouse model of AD–relevant pathophysiology, oral administration of MW01–5–188WH attenuated human amyloid–beta–induced neuroinflammation, synaptic damage, and hippocampal–dependent behavioral deficits. MW01–5–188WH shows no apparent tissue toxicity, rapidly enters the brain after oral administration, and is selective for suppression of CNS inflammation versus peripheral inflammation at comparatively low therapeutic doses. Recent medicinal chemistry refinement of MW01–5–188WH has identified a clinical candidate compound that is currently in development by an industry partner. Results with MW01–5–188WH and its analogs provide an integrative chemical biology causative link supporting the neuroinflammation hypothesis of disease progression, demonstrate that innate immunity responses in brain can be modulated differentially from those of other tissues, and indicate the feasibility of developing efficacious therapies for neurodegenerative disorders by targeting key glial activation pathways.