Shrader, William D. Abstract: Alzheimer's disease (AD) is the largest unmet medical need in the US and the only major cause of death that cannot be prevented, cured, or slowed. Arviat Pharmaceuticals, Inc. is developing oral small-molecule inhibitors of the 12/15-lipoxygenase (12/15-LO) enzyme family to reduce microglia driven neuroinflammation and, thereby, slow progression of AD. Inhibition of 12/15-LO activity to reduce neuroinflammation has been validated in human clinical trials in Parkinson's disease and orphan pediatric neurodegenerative diseases, in human genome wide association studies, and in animal models of AD and other adult neurodegenerative diseases. Vatiquinone™, a first generation 12/15-LO inhibitor discovered and developed by the PI, is now used to treat children with Leigh syndrome, a rare, otherwise fatal pediatric neurodegenerative disease characterized by severe neuroinflammation, microgliosis, and gliotic scarring of the brain. With their extreme neuroinflammation, this pediatric population can be viewed as accelerated models of adult neurodegenerative disease (e.g. AD). Vatiquinone™ is not well-suited for treating AD or Parkinson's disease, leading to the plans, under this proposed SBIR, to develop second-generation oral small-molecule inhibitors of 12/15-LO with significantly greater efficacy than Vatiquinone™. These efforts will leverage existing and generate new intellectual property, covering novel agents potentially suitable for treating large populations with AD and other adult neurodegenerative diseases. In addition to LO inhibitors developed internally, Arviat has an option on a portfolio covering 5 compound families (7 US patents (issued 2013–2019) and several pending applications), which claim compositions of matter with the same novel redox mechanism of action as Vatiquinone™. This proposed Phase I SBIR research will lead to rapid prioritization of compounds from these 6 families, through an iterative screening funnel, consisting of these Specific Aims: (1) To prepare ≥100 compounds, selected to thoroughly sample the patent portfolios; (2) To test these compounds for (i) potency and selectivity as 12/15- LO (vs 5-LO) inhibitors in enzyme assays and (ii) suppression of cytokine production in activated human microglial cultures (iPSC-microglia); (3) To test ≥20 compounds, advanced based on Aim 2 criteria (IC50<50 nM for 12/15-LO, and >500 nM for 5-LO and IC50 ≤75 nM in cellular assays), in a functional neuroprotection assay (prevention of axonal degeneration in NGF-deprived mouse primary neurons); and (4) To test ≥6 compounds, advanced based on the Aim 3 criterion (IC50≤75 nM), for oral bioavailability and brain permeability in rats (criteria for advancement, brain/plasma ratios ≥0.5 and oral availability ≥20%). If successful, this research will identify at least 3 compounds for further evaluation in Phase II, to include synthetic scale-up, toxicology screening, off-target activities, formulation development, conf...