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.
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. alee7@its.jnj.com
Alice
A
Lee-Dutra
Danielle K
DK
Wiener
Kristen L
KL
Arienti
Jing
J
Liu
Neelakandha
N
Mani
Michael K
MK
Ameriks
Frank U
FU
Axe
Damara
D
Gebauer
Pragnya J
PJ
Desai
Steven
S
Nguyen
Mike
M
Randal
Robin L
RL
Thurmond
Siquan
S
Sun
Lars
L
Karlsson
James P
JP
Edwards
Todd K
TK
Jones
Cheryl A
CA
Grice
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