JNJ-39641160 (JNJ39641160) is a peripherally restricted, non-covalent, potent, selective, orally-available Cathepsin S (CatS) inhibitor with Ki of 38 nM (hCatS).
JNJ-39641160 maintains a high selectivity against other closely related cysteine proteases including cathepsins B, C, F, V (L2), K, Z, C, or legumain and the aspartic proteases such as cathepsins E or D.
JNJ-39641160 showed similar potency against human and monkey CatS enzymes, and it exhibited less, albeit significant, activity against mouse and dog CatS enzymes (Ki=160-207 nM).
JNJ-39641160 is only weakly active against rat cathepsin S (Ki=9.6 uM). JNJ-39641160 induced accumulation of the p10Ii with an average IC50 of 294 ± 28 nM, showed similar potency in purified human PBMC with IC50 of 327 nM.
JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen in C57BL/6 mice.
JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice.