Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket

Adrian Huang; Diane Joseph-McCarthy; Frank Lovering; Linhong Sun; Weiheng Wang; Weixin Xu; Yi Zhu; Junqing Cui; Yuhua Zhang; Jeremy I Levin

doi:10.1016/j.bmc.2007.06.031

Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket

Bioorg Med Chem. 2007 Sep 15;15(18):6170-81. doi: 10.1016/j.bmc.2007.06.031. Epub 2007 Jun 20.

Authors

Adrian Huang¹, Diane Joseph-McCarthy, Frank Lovering, Linhong Sun, Weiheng Wang, Weixin Xu, Yi Zhu, Junqing Cui, Yuhua Zhang, Jeremy I Levin

Affiliation

¹ Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. [email protected]

PMID: 17606376
DOI: 10.1016/j.bmc.2007.06.031

Abstract

A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM Proteins / metabolism
ADAM17 Protein
Animals
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology*
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases / metabolism
Mice
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

Enzyme Inhibitors
Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Tumor Necrosis Factor-alpha
ADAM Proteins
Matrix Metalloproteinases
ADAM17 Protein
Adam17 protein, mouse