Structural optimization of azadipeptide nitriles strongly increases association rates and allows the development of selective cathepsin inhibitors.
Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrile inhibitors. A systematic scan with respect to P2 and P3 substituents was carried out. Structural modifications strongly affected the enzyme-inhibitor association (but not dissociation) rate. A combination of optimized P2 and P3 substituents with a methylation of the P3-P2 amide linker resulted in the picomolar cathepsin K inhibitor 19 with remarkable selectivity over cathepsins L, B, and S.
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Maxim
M
Frizler
Friederike
F
Lohr
Norbert
N
Furtmann
Julia
J
Kläs
Michael
M
Gütschow
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D004151:Dipeptides; D009570:Nitriles; D056657:Cathepsin K