The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor.
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
Isabel
Elise
E
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Québec, Canada H9H 3L1. elise_isabel@merck.com
Bateman
Kevin P
KP
Chauret
Nathalie
N
Cromlish
Wanda
W
Desmarais
Sylvie
S
Duong
Le T
LT
Falgueyret
Jean-Pierre
JP
Gauthier
Jacques Yves
JY
Lamontagne
Sonia
S
Lau
Cheuk K
CK
Léger
Serge
S
LeRiche
Tammy
T
Lévesque
Jean-François
JF
Li
Chun Sing
CS
Massé
Frédéric
F
McKay
Daniel J
DJ
Mellon
Christophe
C
Nicoll-Griffith
Deborah A
DA
Oballa
Renata M
RM
Percival
M David
MD
Riendeau
Denis
D
Robichaud
Joël
J
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Seto
Carmai
C
Thérien
Michel
M
Truong
Vouy Linh
VL
Wesolowski
Gregg
G
Young
Robert N
RN
Zamboni
Robert
R
Black
W Cameron
WC
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D011817:Rabbits; D051381:Rats
D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; C552196:MK 0674; D056657:Cathepsin K; C527128:odanacatib