title: Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors.
abstract: 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.
authors.affiliation: Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. jpalmer@rigel.com
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rydzewski
authors.forename: Rohan V
authors.initials: RV
authors.lastname: Mendonca
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Spencer
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Hirschbein
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.forename: Jeri
authors.initials: J
authors.lastname: Beltman
authors.forename: Margaret
authors.initials: M
authors.lastname: Nguyen
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; C509190:Tpsb2 protein, mouse; D012697:Serine Endopeptidases; C509222:Tpsab1 protein, mouse; D053802:Tryptases