Non-hydroxamate 5-phenylpyrimidine-2,4,6-trione derivatives as selective inhibitors of tumor necrosis factor-alpha converting enzyme

James J-W Duan; Zhonghui Lu; Zelda R Wasserman; Rui-Qin Liu; Maryanne B Covington; Carl P Decicco

doi:10.1016/j.bmcl.2005.04.039

Non-hydroxamate 5-phenylpyrimidine-2,4,6-trione derivatives as selective inhibitors of tumor necrosis factor-alpha converting enzyme

Bioorg Med Chem Lett. 2005 Jun 15;15(12):2970-3. doi: 10.1016/j.bmcl.2005.04.039.

Authors

James J-W Duan¹, Zhonghui Lu, Zelda R Wasserman, Rui-Qin Liu, Maryanne B Covington, Carl P Decicco

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. james.duan@bms.com

PMID: 15908214
DOI: 10.1016/j.bmcl.2005.04.039

Abstract

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with a pyrimidine-2,4,6-trione in place of the commonly used hydroxamic acid. These non-hydroxamate TACE inhibitors were developed by incorporating a 4-(2-methyl-4-quinolinylmethoxy)phenyl group, an optimized TACE selective P1' group. Several leads were identified with IC50 values around 100 nM in a porcine TACE assay and selective over MMP-1, -2, -9, -13, and aggrecanase.

MeSH terms

ADAM Proteins
ADAM17 Protein
Animals
Endopeptidases / chemistry
Hydroxamic Acids / chemistry*
Matrix Metalloproteinase Inhibitors*
Metalloendopeptidases / antagonists & inhibitors*
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Swine

Substances

Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Protease Inhibitors
Pyrimidines
Endopeptidases
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein
aggrecanase