Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors

Henry-Georges Lombart; Eric Feyfant; Diane Joseph-McCarthy; Adrian Huang; Frank Lovering; LinHong Sun; Yi Zhu; Congmei Zeng; Yuhua Zhang; Jeremy Levin

doi:10.1016/j.bmcl.2007.05.022

Design and synthesis of 3,3-piperidine hydroxamate analogs as selective TACE inhibitors

Bioorg Med Chem Lett. 2007 Aug 1;17(15):4333-7. doi: 10.1016/j.bmcl.2007.05.022. Epub 2007 May 16.

Authors

Henry-Georges Lombart¹, Eric Feyfant, Diane Joseph-McCarthy, Adrian Huang, Frank Lovering, LinHong Sun, Yi Zhu, Congmei Zeng, Yuhua Zhang, Jeremy Levin

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. hglombart@wyeth.com

PMID: 17531482
DOI: 10.1016/j.bmcl.2007.05.022

Abstract

Structure-based methods were used to design beta-sulfone 3,3-piperidine hydroxamates as TACE inhibitors with the aim of improving selectivity for TACE versus MMP-13. Several compounds in this series were synthesized and evaluated in enzymatic and cell-based assays. These analogs exhibit excellent in vitro potency against isolated TACE enzyme and show good selectivity for TACE over the related metalloproteases MMP-2, -13, and -14.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Models, Molecular

Substances

Enzyme Inhibitors
Hydroxamic Acids
ADAM Proteins
ADAM17 Protein