Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors.
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
Ward
Yancey D
YD
Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA. yward@rdg.boehringer-ingelheim.com
Thomson
David S
DS
Frye
Leah L
LL
Cywin
Charles L
CL
Morwick
Tina
T
Emmanuel
Michel J
MJ
Zindell
Renée
R
McNeil
Daniel
D
Bekkali
Younes
Y
Girardot
Marc
M
Hrapchak
Matt
M
DeTuri
Molly
M
Crane
Kathy
K
White
Della
D
Pav
Susan
S
Wang
Yong
Y
Hao
Ming-Hong
MH
Grygon
Christine A
CA
Labadia
Mark E
ME
Freeman
Dorothy M
DM
Davidson
Walter
W
Hopkins
Jerry L
JL
Brown
Maryanne L
ML
Spero
Denice M
DM
Giradot
Marc
M
D001402:B-Lymphocytes / Q000187:drug effects; D001667:Binding, Competitive; D002403:Cathepsins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D004791:Enzyme Inhibitors; D009570:Nitriles; D002403:Cathepsins; C028217:cathepsin S