title: Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K.
abstract: The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. blackc@merck.com
authors.forename: W Cameron
authors.initials: WC
authors.lastname: Black
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: Dana E
authors.initials: DE
authors.lastname: Davis
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Serge
authors.initials: S
authors.lastname: Léger
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: James T
authors.initials: JT
authors.lastname: Palmer
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.forename: Robert
authors.initials: R
authors.lastname: Zamboni
mesh_terms: D000577:Amides / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D005021:Ethylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004151:Dipeptides; D005021:Ethylamines; D011480:Protease Inhibitors; C032626:trifluoroethylamine; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K