title: Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions.
abstract: A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. Jwiener1@its.jnj.com
authors.forename: John J M
authors.initials: JJ
authors.lastname: Wiener
authors.forename: Alvah T
authors.initials: AT
authors.lastname: Wickboldt
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Wiener
authors.forename: Alice
authors.initials: A
authors.lastname: Lee-Dutra
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: Steven
authors.initials: S
authors.lastname: Nguyen
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Todd K
authors.initials: TK
authors.lastname: Jones
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Grice
mesh_terms: D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D011720:Pyrazoles; D013440:Sulfides; C031280:pyrazole; D002403:Cathepsins; C028217:cathepsin S