Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.
A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
Ameriks
Michael K
MK
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com
Bembenek
Scott D
SD
Burdett
Matthew T
MT
Choong
Ingrid C
IC
Edwards
James P
JP
Gebauer
Damara
D
Gu
Yin
Y
Karlsson
Lars
L
Purkey
Hans E
HE
Staker
Bart L
BL
Sun
Siquan
S
Thurmond
Robin L
RL
Zhu
Jian
J
D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D011720:Pyrazoles; D002403:Cathepsins; C028217:cathepsin S