title: Difluoroethylamines as an amide isostere in inhibitors of cathepsin K.
abstract: The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada. isabel.e@videotron.ca
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: Christophe
authors.initials: C
authors.lastname: Mellon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boyd
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chauret
authors.forename: Denis
authors.initials: D
authors.lastname: Deschênes
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Jacques Yves
authors.initials: JY
authors.lastname: Gauthier
authors.forename: Karine
authors.initials: K
authors.lastname: Khougaz
authors.forename: Cheuk K
authors.initials: CK
authors.lastname: Lau
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Levorse
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Frédéric
authors.initials: F
authors.lastname: Massé
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Bruno
authors.initials: B
authors.lastname: Roy
authors.forename: John
authors.initials: J
authors.lastname: Scheigetz
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; D000577:Amides / Q000737:chemistry; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D005021:Ethylamines; D011480:Protease Inhibitors; D056657:Cathepsin K; C527128:odanacatib