Systemic AA amyloidosis is characterized by the deposition and accumulation of insoluble fibrillar deposits containing the AA amyloid protein in a number of different organs (including heart, kidney, spleen, lungs and/or gastrointestinal tract), whereby such amyloid accumulation leads to marked organ dysfunction. Systemic AA amyloidosis is associated with chronic inflammatory disorders and includes patients with rheumatoid arthritis, osteomyelitis, ankylosing spondylitis, inflammatory bowel diseases, tuberculosis, leprosy, Hodgkin's disease, renal cell carcinoma, and Familial Mediterranean Fever. The consequences of fibrillar AA amyloid deposition in systemic organs are detrimental to the patient, with most patients dying within 3-7 years from disease onset, due to kidney or heart failure. Currently, there is no effective cure or treatment for AA amyloidosis, and new therapeutics are desperately needed. Using various in vitro screening technologies, and an experimental mouse model of AA amyloidosis, we have discovered a new class of small compounds that demonstrate efficacy in significantly arresting fibrillar AA amyloid formation and deposition in systemic organs in a mouse model. In this Phase I SBIR project, we will build on our important initial observations and use in vitro screening methodologies (aim 1) and cell culture (aim 2) to identify small non-toxic compounds with specific structural features important for the inhibition of formation and deposition of fibrillar AA amyloid in tissues. The types of compounds to be tested include both commercially available compounds and specific synthetic analoqs (representing new compositions of matter) that will yield valuable information pertaining to structure-activity relationships for the observed efficacy. The most active non-toxic compounds identified using in vitro screening techniques will then be further tested for efficacy following oral administration utilizing a relevant mouse model of systemic AA amyloidosis. This Phase I SBIR proposal is anticipated to lead to new therapeutic compounds for the treatment of systemic AA amyloidosis found in patients with a variety of chronic inflammatory disorders. [unreadable] [unreadable] [unreadable]