The goal of this project is to develop novel, safe protease inhibitors that can be used as drugs in the treatment of rheumatoid and osteo arthritis. Development of such drugs for human use is a lengthy and expensive process, but the potential market for them is enormous. An effective treatment would attract considerable commercial interest because this disease has generated a multi-billion dollar palliative treatment industry world-wide. There are several proteases which have been causally linked with arthritis. All are candidates for drug design. This project is directed to the inhibition of one class in particular, the sulfur-requiring enzyme cathepsins B, L, and O. There are inhibitors available for these enzymes but they are too toxic to be used in people. The inhibitors of this proposal have been demonstrated in principle, to be non-toxic. The present aim of Phase I is to identify lead candidate inhibitors by a pathophysiological model of cartilage degradation in vitro assays, to scale up the lead candidate syntheses to multi gram levels and to assess the efficacy of this select group of inhibitors (three) in an adjuvant arthritis in vivo model.Proposed commercial application:This proposal is focused on the development of safe and effective treatments for osteo and rheumatoid arthritis. If successful the therapeutics will be submitted for clinical trials in collaboration with a major pharmaceutical company.National Institute of Arthritis and Muscoloskeletal and Skin Diseases (NIAMS)
