Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
Lee-Dutra
Alice
A
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. alee7@its.jnj.com
Wiener
Danielle K
DK
Arienti
Kristen L
KL
Liu
Jing
J
Mani
Neelakandha
N
Ameriks
Michael K
MK
Axe
Frank U
FU
Gebauer
Damara
D
Desai
Pragnya J
PJ
Nguyen
Steven
S
Randal
Mike
M
Thurmond
Robin L
RL
Sun
Siquan
S
Karlsson
Lars
L
Edwards
James P
JP
Jones
Todd K
TK
Grice
Cheryl A
CA
D001665:Binding Sites; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; 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