Systemic AA Amyloidosis Inhibitors

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DESCRIPTION (provided by applicant): Systemic AA Amyloidosis is characterized by the accumulation of insoluble fibril deposits containing the AA amyloid protein in different organs throughout the body including heart, kidney, liver, spleen, lungs, skin and gastrointestinal tract, whereby such amyloid fibril accumulation leads to pronounced organ dysfunction. Systemic AA amyloidosis is associated mostly with chronic inflammatory disorders and includes patients with rheumatoid arthritis, osteomyelitis, ankylosing spondylitis, inflammatory bowl disease, tuberculosis, leprosy, Hodgkin's disease, renal cell carcinoma, and Familial Mediterranean Fever. The consequences of fibrillar AA amyloid deposition in systemic organs are usually fatal to patients, with most patients dying within 3-7 years from disease onset due to kidney or heart failure. Currently there is no effective cure treatment for AA amyloidosis and a new therapeutic is desperately needed for the ~100,000 cases currently in the USA. In our completed Phase I SBIR studies we designed, synthesized and tested our own unique library of small molecule compounds (representing new chemical entities) for inhibition of AA amyloidosis both in vitro and in vivo. Using a variety of in vitro screening methods to identify specific potent inhibitors of AA amyloidosis, we discovered that a number of our small molecule compounds markedly disrupted/inhibited SAA/AA amyloid fibrils in vitro. Using a relevant animal mouse model of experimental AA amyloidosis we now have identified 2 lead compounds (i.e. PTI-19 and 51) that remarkably inhibit AA amyloid deposition in tissues (i.e. spleen, liver and kidney) by >50-60% following oral administration. PTI-19 and 51 represent new chemical entities and our established synthetic routes for the repeated production of each of these compounds demonstrate a pure product (>98% purity) that consists of only 1 compound and 1 stereoisomer [(as determined by detailed analysis including HPLC/mass spec, 1H-NMR, 13C-NMR, DEPT, and x-ray crystallography (for PTI-19)]. These studies suggest that these small molecule lead compounds show great promise for the development of new effective treatments for systemic AA amyloidosis and warrant further investigation as described in this Phase II SBIR project. In proposed Phase II studies we will work with two world class organic chemists and optimize, test and further develop these small molecule compounds (including our 2 lead compounds) that we anticipate will inhibit/retard and cause a clearance of aggregated/fibrillar AA amyloid deposits in humans. In vitro testing against human AA amyloid fibrils will include newly designed analogs optimized for oral bioavailability and enhanced PK characteristics, while maintaining non-toxicity and potent efficacy. Confirmation of each final product synthesized and the possible existence of stereoisomers will be determined using 1H-NMR, 13C-NMR and DEPT. X-ray crystallography will also be used for promising lead compounds in which absolute determination of stereochemistry cannot be fully verified by NMR. Oral administration and time-dependent efficacy for prevention, reduction and clearance of AA amyloid deposits in systemic organs will be assessed using two experimental AA amyloid mouse models. PK and toxicity studies will help us optimize a novel small molecule compound (and its back-up) that will be developed for human clinical trials and commercialization, and that has promise to serve as a new treatment for systemic AA amyloidosis and related diseases. PUBLIC HEALTH RELEVANCE: Systemic AA Amyloidosis is usually a fatal disease characterized by fibrillar amyloid deposition throughout the body that leads to organ dysfunction and eventually death in 3-7 years (due to kidney and/or heart failure). We have designed and discovered new small molecule compounds that effectively reduce/inhibit amyloid deposition in organs in a relevant animal model that mimics the human disease. In this project we intend to develop a new drug (and back-up) for effective treatment of ~100,000 cases of systemic amyloidosis in the USA, for which today there is no real treatment whatsoever.