Acyclic, orally bioavailable ketone-based cathepsin K inhibitors.
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
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
McFadyen
Robert B
RB
Miller
Aaron B
AB
Miller
Larry R
LR
Samano
Vicente
V
Tavares
Francis X
FX
Wells-Knecht
Kevin J
KJ
Wright
Lois L
LL
Zhou
Hui-Qiang Q
HQ
D000284:Administration, Oral; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K