Orally bioavailable small molecule ketoamide-based inhibitors of cathepsin K.
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.
Barrett
David G
DG
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Catalano
John G
JG
Deaton
David N
DN
Long
Stacey T
ST
Miller
Larry R
LR
Tavares
Francis X
FX
Wells-Knecht
Kevin J
KJ
Wright
Lois L
LL
Zhou
Hui-Qiang Q
HQ
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004285:Dogs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship
D000577:Amides; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K