MMP-12 (macrophage elastase) is a member of a family of proteases that target proteins of the extracellular matrix. Matrix metalloproteinases (MMPs) influence tissue remodeling both in healthy growth and development and in the progression of pathological conditions such as arthritis and cancer. Members of the MMP family are specific for different components of the extracellular matrix and thus contribute to different disease states. They share a strongly conserved active site, including a catalytic zinc ion, coordinated by three conserved histidine side chains. The active site is contained within a groove along one face of the protein, the substrate binding cleft, that accommodates the protein chain to be cleaved. One wall of the substrate binding cleft is formed by the specificity loop, the loop between helix B and helix C. This loop varies in composition and length among members of the MMP family and contributes to the substrate specificity of the individual MMPs by forming much of the S10 binding pocket. MMP-12 was identified as the elastase activity produced by alveolar macrophages (Shapiro et al. 1993), although it shows activity against a range of basement membrane components, including fibronectin, laminin, entactin, chondroitan sulfate, and heparin sulfate (Gronski et al. 1997). Patients suffering from chronic obstructive pulmonary disease (COPD) show higher levels of MMP-12 in lung tissue and bronchoalveolar lavage (Molet et al. 2005). MMP-12 knockout mice are resistant to emphysema even when exposed to cigarette smoke (Hautamaki et al. 1997). These observations suggest that an MMP-12 inhibitor is a potentially disease-modifying treatment for COPD. Previous MMP inhibitors have been plagued with musculoskeletal side effects (Wojtowicz-Praga 1998), presumably due to a lack of selectivity for the target enzyme. For many compounds, this lack of selectivity can be traced to a hydroxamate functionality, which provides affinity by chelating the catalytic zinc ion but prevents specificity, since all the enzymes in this family contain this zinc. To avoid these specificity issues, we have been interested in developing an inhibitor lacking the M. A. Markus (&) B. Dwyer S. Wolfrom K. Malakian J. Wilhelm D. H. H. Tsao Structural Biology and Computational Chemistry, Chemical and Screening Sciences, Wyeth Research, 87 CambridgePark Drive, Cambridge, MA 02140, USA e-mail: mmarkus@wyeth.com