Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitor s. Inhibitor design was based on a positional scanning approach of the amin o acids present within a template molecule, previously shown to be an MMP i nhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of mo re focused parallel and/or combinatorial libraries of MMP inhibitors as a m eans to accelerate the lead discovery process. This paper reports the succe ss of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these position al scanning libraries, we have obtained important SAR information, in parti cular, pharmacophores with the ability to impart selectivity for particular MMP species.