Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1.
Cathepsins are known to have many important physiological roles and provide a viable target for inhibition. Fluorobenzoyl dipeptide derivatives were synthesized and tested for biological activity in an effort to find an efficient inhibitor of the cysteine protease cathepsin L. Thirty-six novel inhibitors (1-36) were synthesized from protected amino acids via the standard DCC/HOBt coupling protocol, containing a benzyl ester or a nitrile as an electrophilic warhead. The activity of the inhibitors was evaluated against cathepsin L and IC50 values calculated. Modification of both amino acids and terminal groups afforded compounds with single digit micromolar inhibition. Results utilizing the benzoyl-L-leucine-glycine nitrile backbone are comparable to that for the commercially available inhibitor 39.
Moran
Brian W
BW
School of Chemical Sciences, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
Anderson
Frankie P
FP
Ruth
Deborah M
DM
Fágáin
Ciarán O
CO
Dalton
John P
JP
Kenny
Peter T M
PT
D000818:Animals; D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005210:Fasciola hepatica / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013055:Spectrophotometry, Infrared
D015853:Cysteine Proteinase Inhibitors; D056668:Cathepsin L