Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors.
Using a scaleable, directed library approach based on orthogonally protected advanced intermediates, we have prepared a series of potent keto-1,2,4-oxadiazoles designed to explore the P(2) binding pocket of human mast cell tryptase, while building in a high degree of selectivity over human trypsin and other serine proteases.
Palmer
James T
JT
Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. jpalmer@rigel.com
Rydzewski
Robert M
RM
Mendonca
Rohan V
RV
Sperandio
David
D
Spencer
Jeffrey R
JR
Hirschbein
Bernard L
BL
Lohman
Julia
J
Beltman
Jeri
J
Nguyen
Margaret
M
Liu
Liang
L
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D008407:Mast Cells / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053802:Tryptases
D004791:Enzyme Inhibitors; D010069:Oxadiazoles; C509190:Tpsb2 protein, mouse; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases