Discovery of novel hydantoins as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
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.
Sheppeck
James E
JE
Bristol-Myers Squibb Pharmaceutical Research Institute, Discovery Chemistry, PO Box 4000, Princeton, NJ 08543-4000, USA. jim.sheppeck@bms.com
Gilmore
John L
JL
Yang
Anle
A
Chen
Xiao-Tao
XT
Xue
Chu-Biao
CB
Roderick
John
J
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Decicco
Carl P
CP
Duan
James J-W
JJ
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D015195:Drug Design; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D006827:Hydantoins; D051722:ADAM Proteins; D000072198:ADAM17 Protein