Human neutrophil elastase (HNE) is a serine protease with broad substrate specificity. It is linked to the pathologic processes of a variety of inflammatory diseases, including idiopathic pulmonary fibrosis, rheumatoid arthritis, adult respiratory distress syndrome, and cystic fibrosis. This highly active protease is able to break down mechanically important structures of the body’s own cellular matrix (e.g., proteins such as elastin and collagen), as well as proteins foreign to the body (e.g., outer cell wall proteins of Gram-negative bacteria) . Accordingly, HNE is a potential target for the treatment of diseases and various HNE inhibitors have been described [2, 3].
Bayer has developed a potent, selective, cell-permeable HNE inhibitor, BAY-678 [reference 4 compound 20; reference 5 compound 23, see also references 6] and has made this available for distribution by the SGC. BAY-678 (R-enantiomer) inhibits HNE reversibly (and in a non-reactive manner) with an in vitro IC50 = 20 nM and Ki = 15 nM. (The S-enantiomer BAY-677 inhibits HNE with IC50 > 2000 nM and thus may be used as a control compound.) BAY-678 has more than 2,000-fold selectivity in a panel of 21 serine proteases, and there is no significant inhibition against 7 serine/threonine kinases and 64 pharmacologically relevant proteins. BAY-678 and BAY-677 showed no activity against the CEREP panel of 55 GPCRs and Ion Channels when tested at a concentration of 10uM
BAY-678 is cell-permeable, effluxratio = 2.7, and has a favorable pharmacokinetic profile. The cell based activity of BAY-678 on HNE is not relevant and has not been measured. Efficacy was demonstrated in acute in vivo models, for example, protease-induced acute lung injury (ALI) in mice, where exogenous HNE in the mouse lung was inhibited with Ki = 15 nM after oral administration.
Physiochemical Properties BAY-678