Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors

James T Palmer; Robert M Rydzewski; Rohan V Mendonca; David Sperandio; Jeffrey R Spencer; Bernard L Hirschbein; Julia Lohman; Jeri Beltman; Margaret Nguyen; Liang Liu

doi:10.1016/j.bmcl.2006.04.013

Design and synthesis of selective keto-1,2,4-oxadiazole-based tryptase inhibitors

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3434-9. doi: 10.1016/j.bmcl.2006.04.013. Epub 2006 Apr 27.

Authors

James T Palmer¹, Robert M Rydzewski, Rohan V Mendonca, David Sperandio, Jeffrey R Spencer, Bernard L Hirschbein, Julia Lohman, Jeri Beltman, Margaret Nguyen, Liang Liu

Affiliation

¹ Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. [email protected]

PMID: 16644215
DOI: 10.1016/j.bmcl.2006.04.013

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.

MeSH terms

Animals
Binding Sites / drug effects
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Haplorhini
Humans
Mast Cells / drug effects*
Mast Cells / enzymology
Mice
Molecular Structure
Oxadiazoles / chemical synthesis*
Oxadiazoles / chemistry
Oxadiazoles / pharmacology
Serine Endopeptidases / drug effects*
Stereoisomerism
Structure-Activity Relationship
Tryptases

Substances

Enzyme Inhibitors
Oxadiazoles
Tpsb2 protein, mouse
Serine Endopeptidases
Tpsab1 protein, mouse
Tryptases