Design and synthesis of butynyloxyphenyl β-sulfone piperidine hydroxamates as TACE inhibitors

A series of butynyloxyphenyl β-sulfone piperidine hydroxamate TACE inhibitors was designed and synthesized. The resulting structure–activity relationship and MMP selectivity of the series were examined. Of the compounds investigated, 17s has excellent in vitro potency against isolated TACE enzyme, s...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-08, Vol.16 (15), p.3927-3931
Main Authors: Park, Kaapjoo, Aplasca, Alexis, Du, Mila T., Sun, LinHong, Zhu, Yi, Zhang, Yuhua, Levin, Jeremy I.
Format: Article
Language:English
Subjects:
ADAM Proteins - antagonists & inhibitors
ADAM17 Protein
Animals
Biological and medical sciences
Drug Design
Medical sciences
Mice
Miscellaneous
MMP selectivity
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Structure-Activity Relationship
TACE inhibitors
β-Sulfone piperidine hydroxamates
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Summary:A series of butynyloxyphenyl β-sulfone piperidine hydroxamate TACE inhibitors was designed and synthesized. The resulting structure–activity relationship and MMP selectivity of the series were examined. Of the compounds investigated, 17s has excellent in vitro potency against isolated TACE enzyme, shows good selectivity over MMP-1, -2, -7, -8, -9, -13, and -14, and oral activity in an in vivo mouse model of TNF-α production.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.05.026