Exploration of the P1 SAR of aldehyde cathepsin K inhibitors.
The synthesis and biological activity of a series of aldehyde inhibitors of cathepsin K are reported. Exploration of the properties of the S(1) subsite with a series of alpha-amino aldehyde derivatives substituted at the P(1) position afforded compounds with cathepsin K IC(50)s between 52 microM and 15 nM.
Catalano
John G
JG
Department of Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
Deaton
David N
DN
Furfine
Eric S
ES
Hassell
Annie M
AM
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Shewchuk
Lisa M
LM
Willard
Derril H
DH
Wright
Lois L
LL
D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000447:Aldehydes; D011480:Protease Inhibitors; D002403:Cathepsins; D056657:Cathepsin K