Metzincin Modulators

This chapter addresses the most recent developments in MMP and ADAM protease inhibitors. Multiple reviews focus on past medicinal chemistry efforts in the development of metzincin inhibitors. The chapter focuses on the advances made using approaches alternative to zinc-binding in the MMPs' and ADAMs' active sites with an emphasis on rational design. It is possible to achieve inhibition of metzincins via secondary binding site mechanism using rational approaches or combination of rational approaches with high-throughput ones. The chapter demonstrates the benefits of a rational design of an exosite-binding substrate that led to a discovery of a novel exosite-binding inhibitor. It focuses on design approaches using endogenous inhibitors of metzincins tissue inhibitors of metalloproteinases (TIMPs). Development of rational approaches to discovery and development of substrate-selective inhibitors presents an interesting new direction for future metzincin inhibition studies.