Cathepsins are a family of proteases that have been implicated in many diseases.
Virobay compounds are highly potent, orally active and drug-like; addressing common problems in the design of cathepsin inhibitors.
The cleavage of proteins by proteases is a critical process in the pathogenesis of atherosclerosis. Proteases have been implicated in the disruption of the medial elastic lamina, macrophage and smooth muscle cell migration, intimal neoangiogenesis and destabilization of the fibrous cap of atherosclerotic plaques.
Cathepsin S is a highly potent cysteine protease which possesses both elastolytic and collagenolytic properties. Cathepsin S has also been shown to cleave ApoB-100 leading to the fusion of LDL particles which promotes the formation of fatty streaks.Cathepsin S can be expressed by all the cells which have been associated with the atherosclerotic process and its expression is stimulated by several mediators which are believed to upregulated in plaque. In human atheromatous arteries, mRNA for cathepsin S is upregulated and immunoreactive cathepsin S is overexpressed in foam cells, intima and smooth muscle cells. Furthermore, serum levels of cathepsin S are elevated in patients with atherosclerosis.
In murine models of atherosclerosis, it has been shown that cathepsin S deficiency (in Cat S-/- mice), in either LDLR-/- mice or ApoE-/- mice, results in a dramatic reduction in atherosclerosis and also in the number of plaque ruptures.
Recently, a Virobay selective cathepsin S inhibitor was evaluated in ApoE-/- mice fed a high fat diet. After 8 weeks of dosing with the cathepsin S inhibitor, the size of atherosclerotic plaques were reduced by 68% in female mice (36% in male mice), plaque macrophages were reduced (40% reduction in females, 47% reduction in males) and buried fibrous caps were diminished, with 86% less in females, 50% less in males (Samokhin et al, 2010).