N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1' isobutyl substitution.
N-Hydroxyformamide-class metalloprotease inhibitors were designed and synthesized, which have potent broad-spectrum activity versus matrix metalloproteases and TNF-alpha converting enzyme (TACE). Compound 13c possesses good oral and intravenous pharmacokinetics in the rat and dog.
Musso
D L
DL
GlaxoSmithKline Research and Development, Five Moore Drive, Research Triangle Park, NC 27709, USA. dm12907@glaxowellcome.com
Andersen
M W
MW
Andrews
R C
RC
Austin
R
R
Beaudet
E J
EJ
Becherer
J D
JD
Bubacz
D G
DG
Bickett
D M
DM
Chan
J H
JH
Conway
J G
JG
Cowan
D J
DJ
Gaul
M D
MD
Glennon
K C
KC
Hedeen
K M
KM
Lambert
M H
MH
Leesnitzer
M A
MA
McDougald
D L
DL
Mitchell
J L
JL
Moss
M L
ML
Rabinowitz
M H
MH
Rizzolio
M C
MC
Schaller
L T
LT
Stanford
J B
JB
Tippin
T
T
Warner
J R
JR
Whitesell
L G
LG
Wiethe
R W
RW
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005559:Formamides / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005559:Formamides; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat