The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors.
A novel series of TNF-alpha convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Rosner
Kristin E
KE
Department of Medicinal Chemistry, Schering-Plough Research Institute Cambridge, 320 Bent Street, Cambridge, MA 02141, United States.
Guo
Zhuyan
Z
Orth
Peter
P
Shipps
Gerald W
GW
Belanger
David B
DB
Chan
Tin Yau
TY
Curran
Patrick J
PJ
Dai
Chaoyang
C
Deng
Yongqi
Y
Girijavallabhan
Vinay M
VM
Hong
Liwu
L
Lavey
Brian J
BJ
Lee
Joe F
JF
Li
Dansu
D
Liu
Zhidan
Z
Popovici-Muller
Janeta
J
Ting
Pauline C
PC
Vaccaro
Henry
H
Wang
Li
L
Wang
Tong
T
Yu
Wensheng
W
Zhou
Guowei
G
Niu
Xiaoda
X
Sun
Jing
J
Kozlowski
Joseph A
JA
Lundell
Daniel J
DJ
Madison
Vincent
V
McKittrick
Brian
B
Piwinski
John J
JJ
Shih
Neng-Yang
NY
Arshad Siddiqui
M
M
Strickland
Corey O
CO
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000072198:ADAM17 Protein; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013644:Tartrates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D011480:Protease Inhibitors; D013644:Tartrates; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human