A structural screening approach to ketoamide-based inhibitors of cathepsin K.
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.
Barrett
David G
DG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA.
Catalano
John G
JG
Deaton
David N
DN
Long
Stacey T
ST
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Wells-Knecht
Kevin J
KJ
Wright
Lois L
LL
D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K