Identification of a potent and selective non-basic cathepsin K inhibitor.
Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
Li
Chun Sing
CS
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. chunsing_li@merck.com
Deschenes
Denis
D
Desmarais
Sylvie
S
Falgueyret
Jean-Pierre
JP
Gauthier
Jacques Yves
JY
Kimmel
Donald B
DB
Léger
Serge
S
Massé
Frédéric
F
McGrath
Mary E
ME
McKay
Daniel J
DJ
Percival
M David
MD
Riendeau
Denis
D
Rodan
Sevgi B
SB
Thérien
Michel
M
Truong
Vouy-Linh
VL
Wesolowski
Gregg
G
Zamboni
Robert
R
Black
W Cameron
WC
D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D008958:Models, Molecular; D010052:Ovariectomy
D015853:Cysteine Proteinase Inhibitors; D002403:Cathepsins; D056657:Cathepsin K