Inhibitors of proteases can provide novel therapeutic agents to the treatment of a variety of diseases. Over the last few years, we have been engaged in the development of new solid-phase syntheses leading to the identification of several protease inhibitors. The combinatorial projects we are involved in are broad, including the solid phase synthesis of templates such as the cyclic peptide Oscillamide Y and analogues (1) and the solid phase generation of amidine derivatives (2).

These projects are carried out in collaboration with several pharmaceutical companies and the library generation mainly takes place using a "split and mix method" strategy such that each distinct "bead" of the support will contain only a single compound (libraries size: 400-600 compounds).

Finally, we are currently developing solid-phase organic syntheses and combinatorial approach for the generation of libraries of peptide derivatives containing C-terminal aldehydes for lead optimisation of serine-proteases inhibitors (3).

(1) I. Marsh, S. Teague, M. Bradley, J. Org. Chem., 1997, 62, 6199-6203.
(2) P. Roussel, I. Mathews, P. Kane, M. Bradley, Tetrahedron Lett., 1997, 34, 4861-4864.
(3) P. Page, I. Walters, S. Teague, M. Bradley, J. Org. Chem., 1999, 64, 794-799.