Design and synthesis of dipeptidyl nitriles as potent, selective, and reversible inhibitors of cathepsin C.
A series of dipeptide nitriles with a thienyl alanine in P2 were identified as potent and selective cathepsin C inhibitors. Incorporation of a substituted cyclopropyl moiety in P1 effectively protects these derivatives against hydrolase activity in whole blood.
Guay
Daniel
D
Department of Medicinal Chemistry, Merck Frosst Canada & Co., 16711 Trans Canada Hwy, Kirkland, QC, Canada H9H 3L1.
Beaulieu
Christian
C
Truchon
Jean-Francois
JF
Jagadeeswar Reddy
T
T
Zamboni
Robert
R
Bayly
Christopher I
CI
Methot
Nathalie
N
Rubin
Joel
J
Ethier
Diane
D
David Percival
M
M
D000818:Animals; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D004151:Dipeptides / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009570:Nitriles / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004151:Dipeptides; D009570:Nitriles; D020789:Cathepsin C