Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

James E Sheppeck 2nd; John L Gilmore; Anle Yang; Xiao-Tao Chen; Chu-Biao Xue; John Roderick; Rui-Qin Liu; Maryanne B Covington; Carl P Decicco; James J-W Duan

doi:10.1016/j.bmcl.2006.11.089

Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE)

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1413-7. doi: 10.1016/j.bmcl.2006.11.089. Epub 2006 Dec 2.

Authors

James E Sheppeck 2nd¹, John L Gilmore, Anle Yang, Xiao-Tao Chen, Chu-Biao Xue, John Roderick, Rui-Qin Liu, Maryanne B Covington, Carl P Decicco, James J-W Duan

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, Discovery Chemistry, PO Box 4000, Princeton, NJ 08543-4000, USA. jim.sheppeck@bms.com

PMID: 17188863
DOI: 10.1016/j.bmcl.2006.11.089

Abstract

A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.

MeSH terms

ADAM Proteins / antagonists & inhibitors*
ADAM17 Protein
Animals
Drug Design
Hydantoins / chemical synthesis*
Hydantoins / pharmacology*
Inhibitory Concentration 50
Structure-Activity Relationship
Substrate Specificity
Swine

Substances

Hydantoins
ADAM Proteins
ADAM17 Protein