Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors

John L Gilmore; Bryan W King; Cathy Harris; Thomas Maduskuie; Stephen E Mercer; Rui-Qin Liu; Maryanne B Covington; Mingxin Qian; Maria D Ribadeneria; Krishna Vaddi; James M Trzaskos; Robert C Newton; Carl P Decicco; James J-W Duan

doi:10.1016/j.bmcl.2006.02.015

Synthesis and structure-activity relationship of a novel, achiral series of TNF-alpha converting enzyme inhibitors

Bioorg Med Chem Lett. 2006 May 15;16(10):2699-704. doi: 10.1016/j.bmcl.2006.02.015. Epub 2006 Mar 3.

Authors

John L Gilmore¹, Bryan W King, Cathy Harris, Thomas Maduskuie, Stephen E Mercer, Rui-Qin Liu, Maryanne B Covington, Mingxin Qian, Maria D Ribadeneria, Krishna Vaddi, James M Trzaskos, Robert C Newton, Carl P Decicco, James J-W Duan

Affiliation

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

PMID: 16516466
DOI: 10.1016/j.bmcl.2006.02.015

Abstract

A novel series of achiral TNF-alpha converting enzyme (TACE) inhibitors has been discovered. These compounds exhibited activities from 0.35 to 11nM in a porcine TACE assay and inhibited TNF-alpha production in an LPS-stimulated whole blood assay with an IC(50) value of 23nM for the most potent one. They also have excellent selectivities over related metalloproteases including aggrecanases.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Animals
Cell Line
Cyclization
Humans
Mice
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*
Stereoisomerism
Structure-Activity Relationship

Substances

Protease Inhibitors
ADAM Proteins
ADAM17 Protein
ADAM17 protein, human
Adam17 protein, mouse