Exploration of the P2-P3 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 S2 and S3 subsites with a series of carbamate derivatized norleucine aldehydes substituted at the P2 and P3 positions afforded analogs with cathepsin K IC50s between 600 nM and 130 pM.
Boros
Eric E
EE
Department of Medicinal Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
Deaton
David N
DN
Hassell
Anne M
AM
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Paulick
Margot G
MG
Shewchuk
Lisa M
LM
Thompson
James B
JB
Willard
Derril H
DH
Wright
Lois L
LL
D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D009646:Norleucine / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000447:Aldehydes; D002219:Carbamates; D011480:Protease Inhibitors; D009646:Norleucine; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K