Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions.
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.
Wiener
John J M
JJ
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. Jwiener1@its.jnj.com
Wickboldt
Alvah T
AT
Wiener
Danielle K
DK
Lee-Dutra
Alice
A
Edwards
James P
JP
Karlsson
Lars
L
Nguyen
Steven
S
Sun
Siquan
S
Jones
Todd K
TK
Grice
Cheryl A
CA
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*
D011480:Protease Inhibitors; D011720:Pyrazoles; D013440:Sulfides; C031280:pyrazole; D002403:Cathepsins; C028217:cathepsin S