Discovery of potent, selective human granzyme B inhibitors that inhibit CTL mediated apoptosis.
A novel class of small molecule human granzyme B inhibitors is reported. Compound 20 has a K(i) of 7 nM against human granzyme B and blocks CTL mediated apoptosis with an IC(50) of 3 micromolar.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. willoughby@merk.com
Christopher A
CA
Willoughby
Herbert G
HG
Bull
Margarita
M
Garcia-Calvo
Joanne
J
Jiang
Kevin T
KT
Chapman
Nancy A
NA
Thornberry
D017209:Apoptosis / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015195:Drug Design; D053804:Granzymes; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology*
D015842:Serine Proteinase Inhibitors; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases