Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket.
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
Department of Medicinal Chemistry, Schering Plough Research Institute, Kenilworth, NJ 07033, USA. robert.mazzola@spcorp.com
Robert D
RD
Mazzola
Zhaoning
Z
Zhu
Lisa
L
Sinning
Brian
B
McKittrick
Brian
B
Lavey
James
J
Spitler
Joseph
J
Kozlowski
Shih
S
Neng-Yang
Guowei
G
Zhou
Zhuyan
Z
Guo
Peter
P
Orth
Vincent
V
Madison
Jing
J
Sun
Daniel
D
Lundell
Xiaoda
X
Niu
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D055808:Drug Discovery; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat