title: The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor.
abstract: 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.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Québec, Canada H9H 3L1. elise_isabel@merck.com
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bateman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Wanda
authors.initials: W
authors.lastname: Cromlish
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: Sonia
authors.initials: S
authors.lastname: Lamontagne
authors.forename: Cheuk K
authors.initials: CK
authors.lastname: Lau
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Tammy
authors.initials: T
authors.lastname: LeRiche
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McKay
authors.forename: Christophe
authors.initials: C
authors.lastname: Mellon
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Rodan
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Carmai
authors.initials: C
authors.lastname: Seto
authors.forename: Michel
authors.initials: M
authors.lastname: Thérien
authors.forename: Vouy Linh
authors.initials: VL
authors.lastname: Truong
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
mesh_terms: 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
chemical_list: D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; C552196:MK 0674; D056657:Cathepsin K; C527128:odanacatib