Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K.
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.
Black
W Cameron
WC
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Que., Canada H9R 4P8. blackc@merck.com
Bayly
Christopher I
CI
Davis
Dana E
DE
Desmarais
Sylvie
S
Falgueyret
Jean-Pierre
JP
Léger
Serge
S
Li
Chun Sing
CS
Massé
Frédéric
F
McKay
Daniel J
DJ
Palmer
James T
JT
Percival
M David
MD
Robichaud
Joël
J
Tsou
Nancy
N
Zamboni
Robert
R
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
D000577:Amides; D004151:Dipeptides; D005021:Ethylamines; D011480:Protease Inhibitors; C032626:trifluoroethylamine; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K