pIC50: 7.9, 6.7, 6.0, 5.5 and 5.2 for Cathepsin (L, L2, S, K, B), respectively

Cathepsin Inhibitor 1 is an inhibitor of Cathepsin. Osteoarthritis is currently recognized as a chronic degenerative disease, which is caused by the loss of articular cartilage and damage to underlying bone, resulting in joint instability and pain. The lysosomal cysteine protease2 Cathepsin L (CatL) is found to be a potential target for intervention in treatment of osteoarthritis. After secreted into the extracellular matrix, CatL can degrade proteoglycans such as aggrecan4 and type II collagen, which are the major components of articular cartilage.

In vitro: The CatL pIC50 value of Cathepsin Inhibitor 1 was found to exceed that of its analog by 1.6 units. Moreover, CatS (ΔpIC50 = -0.1) and CatL2 (ΔpIC50 = 0.5) were much less sensitive to the structural change of Cathepsin Inhibitor 1, leading to an improved selectivity profile relative to its analog. Cathepsin Inhibitor 1 was as least as selective with respect to CatB and CatS as previously described CatL inhibitors. The crystal structure of its another analog bound to CatL provided the rationale for the SAR observed for Cathepsin Inhibitor 1. The 1-methyl group of the pyrazole made some contact with Leu69 and appeared to force the pyrazole ring out of co-planarity with the amide, likely functioning as a conformational lock [1].

In vivo: So far, there is no in vivo animal data available for Cathepsin Inhibitor 1 is an inhibitor of Cathepsin.

Clinical trial: N/A

Reference:
[1] Asaad N, Bethel PA, Coulson MD, Dawson JE, Ford SJ, Gerhardt S, Grist M, Hamlin GA, James MJ, Jones EV, Karoutchi GI, Kenny PW, Morley AD, Oldham K,Rankine N, Ryan D, Wells SL, Wood L, Augustin M, Krapp S, Simader H, Steinbacher S.  Dipeptidyl nitrile inhibitors of Cathepsin L. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4280-3.