The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K.
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
Gauthier
Jacques Yves
JY
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Que., Canada.
Chauret
Nathalie
N
Cromlish
Wanda
W
Desmarais
Sylvie
S
Duong
Le T
LT
Falgueyret
Jean-Pierre
JP
Kimmel
Donald B
DB
Lamontagne
Sonia
S
Léger
Serge
S
LeRiche
Tammy
T
Li
Chun Sing
CS
Massé
Frédéric
F
McKay
Daniel J
DJ
Nicoll-Griffith
Deborah A
DA
Oballa
Renata M
RM
Palmer
James T
JT
Percival
M David
MD
Riendeau
Denis
D
Robichaud
Joel
J
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Seto
Carmai
C
Thérien
Michel
M
Truong
Vouy-Linh
VL
Venuti
Michael C
MC
Wesolowski
Gregg
G
Young
Robert N
RN
Zamboni
Robert
R
Black
W Cameron
WC
D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000187:drug effects / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D012867:Skin / Q000166:cytology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
D001381:Azepines; D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; C527129:L-873724; D013450:Sulfones; D003094:Collagen; C509706:relacatib; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C527128:odanacatib