Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease.
Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease.
Merck Research Laboratories, Kirkland, QC, Canada. beaulieu.ch@videotron.ca
Christian
C
Beaulieu
Elise
E
Isabel
Angélique
A
Fortier
Frédéric
F
Massé
Christophe
C
Mellon
Nathalie
N
Méthot
Momar
M
Ndao
Deborah
D
Nicoll-Griffith
Doris
D
Lee
Hyeram
H
Park
W Cameron
WC
Black
D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D057056:Cysteine Proteases / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D015800:Protozoan Proteins; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D002403:Cathepsins; D057056:Cysteine Proteases; D003546:Cysteine Endopeptidases; C063214:cruzipain; D014633:Valine