Design of small molecule ketoamide-based inhibitors of cathepsin K.
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption.
Catalano
John G
JG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Deaton
David N
DN
Long
Stacey T
ST
McFadyen
Robert B
RB
Miller
Larry R
LR
Payne
J Alan
JA
Wells-Knecht
Kevin J
KJ
Wright
Lois L
LL
D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D024042:Collagen Type I / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D013329:Structure-Activity Relationship
D024042:Collagen Type I; D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K