title: Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors.
abstract: A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Gustin
authors.forename: Clark A
authors.initials: CA
authors.lastname: Sehon
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.forename: Haripada
authors.initials: H
authors.lastname: Khatuya
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
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; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles; D011725:Pyridines; D002403:Cathepsins; C028217:cathepsin S