Keto-1,3,4-oxadiazoles as cathepsin K inhibitors.
We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis.
Palmer
James T
JT
Celera Genomics, Inc., 180 Kimball Way, South San Francisco, CA 94080, USA. jim.palmer@celera.com
Hirschbein
Bernard L
BL
Cheung
Harry
H
McCarter
John
J
Janc
James W
JW
Yu
Z Walter
ZW
Wesolowski
Gregg
G
D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D011480:Protease Inhibitors; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat