Synthesis and biological activity of piperazine-based dual MMP-13 and TNF-alpha converting enzyme inhibitors.
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group.
Letavic
Michael A
MA
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. michael_a_letavic@groton.pfizer.com
Barberia
John T
JT
Carty
Thomas J
TJ
Hardink
Joel R
JR
Liras
Jennifer
J
Lopresti-Morrow
Lori L
LL
Mitchell
Peter G
PG
Noe
Mark C
MC
Reeves
Lisa M
LM
Snow
Sheri L
SL
Stam
Ethan J
EJ
Sweeney
Francis J
FJ
Vaughn
Marcie L
ML
Yu
Chul H
CH
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D017364:Collagenases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507083:Mmp13 protein, rat; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat