Discovery of low nanomolar non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC(50) of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.
Duan
James J-W
JJ
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. duan@bms.com
Chen
Lihua
L
Lu
Zhonghui
Z
Jiang
Bin
B
Asakawa
Naoyuki
N
Sheppeck
James E
JE
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Pitts
William
W
Kim
Soong-Hoon
SH
Decicco
Carl P
CP
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D001463:Barbiturates; D001549:Benzamides; D006877:Hydroxamic Acids; C519012:N-(4-(methanesulfonylpiperazin-1-yl)-2,4,6-trioxopyrimidin-4-ylmethyl)-4-((2-methylquinolin-4-yl)methoxy)benzamide; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein