Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside (UCR) have developed novel MMP-12 inhibitors with single-digit nanomolar activity. These agents, are highly selective for MMP-12 with appreciable inhibition of only MMP-3. When compared to a known MMP-12 inhibitor, MMP408, the UCR MMP-12 inhibitors are 5 times more potent than MMP408.To examine their efficacy, the UCR MMP-12 inhibitors were tested in a well-established murine model of elastase-induced emphysema. After treatment, it was determined that the mice treated with the MMP-12 inhibitors exhibited significantly less lung damage than the controls. Fig. 1 Docked geometry of one of the UCR MMP-12 inhibitors in complex with MMP-12. Fig. 2 Effects of MMP-12 inhibition on lung tissue destruction in a murine model of elastase-induced emphysema. Mice were challenged with a single intranasal instillation of porcine pancreatic elastase (PPE), then treated daily for 7 days with vehicle control or MMP-12 inhibitors MMP408, compound 25, or compound 26. After 21 days, the mice were examined and data gathered on how they responded. Mice exposed to PPE but treated with MMP-12 inhibitors (MMP-408, compound 25, or compound 26) exhibited a significant decrease in emphysema-like pathology compared to PPE + vehicle-treated mice, with measurements for mice treated with PPE + MMP-12 inhibitors exhibiting no significant differences compared to the control, saline treated mice.