title: Identification of a potent and selective noncovalent cathepsin S inhibitor.
abstract: Cathepsin S is considered crucial for normal presentation of major histocompatibility complex (MHC) class II-restricted antigens by antigen presenting cells to CD4+ T cells. It is a key enzyme for the degradation of the class II-associated invariant chain, a process that is required for effective antigen loading of class II molecules. Here, we report a selective, orally available, high-affinity cathepsin S inhibitor, 1-[3-[4-(6-Chloro-2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl]-4,5,6,7-tetrahydro-5-(methylsulfonyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine. (JNJ 10329670), that represents a novel class of immunosuppressive compounds. JNJ 10329670 is a highly potent (Ki of approximately 30 nM), nonpeptidic, noncovalent inhibitor of human cathepsin S, but it is much less active against the mouse, dog, monkey, and bovine enzymes. The compound is inactive against other proteases, including the closely related cathepsins L, F, and K. This selectivity makes JNJ 10329670 an excellent tool for exploring the role of cathepsin S in human systems. Treatment of human B cell lines and primary human dendritic cells with JNJ 10329670 resulted in the accumulation of the p10 fragment of the invariant chain (IC50 of approximately 1 microM). In contrast, inhibition of invariant chain proteolysis was much less effective in a human monocytic cell line, suggesting that other enzymes may degrade the invariant chain in this cell type. JNJ 10329670 was shown to block the proteolysis of the invariant chain in vivo by using immunocompromised mice injected with human peripheral blood mononuclear cells (PBMCs). Furthermore, this inhibitor blocks the presentation of tetanus toxoid and giant ragweed by human PBMCs. The properties of JNJ 10329670 make it a candidate for immunosuppressive therapy of allergies and autoimmune diseases.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development L.L.C., San Diego, California, USA. rthurmon@prdus.jnj.com
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Baker
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Jason P
authors.initials: JP
authors.lastname: Riley
authors.forename: Kacy N
authors.initials: KN
authors.lastname: Williams
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D000882:Haplorhini; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D051379:Mice; D023421:Models, Animal; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C481342:1-(3-(4-(6-Chloro-2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl)propyl)-4,5,6,7-tetrahydro-5-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo(4,3-c)pyridine; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D002403:Cathepsins; C028217:cathepsin S