This proposal aims to develop novel chemicals as AD therapeutics targeting inflammatory processes, thus responding to a specific priority within the "Drug discovery and preclinical development" RFP as part of the Biotechnology Development Program. We identified through HTS novel agonist and antagonists with generally favourable CNS drug-like properties, which we believe is a first in the CX3CR1 field. We propose to conduct a 12 month Medicinal Chemistry program to establish SAR, select the most promising chemotypes, and generate tool molecules suitable for in vivo testing in AD models. Since the field is not certain for CX3CR1 or neuroinflammation in general how best to modulate it for maximal therapeutic benefit, we are committed to developing both agonists and antagonists that can be used to address these questions empirically. We have in place a team of experienced, highly skilled medicinal chemists and pharmacologists that are veterans of the pharmaceutical industry and have a fully operational screening funnel.